Cathepsin cysteine protease inhibitors

ABSTRACT

This invention relates to class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis. They have the following structure: Formula (I).

BACKGROUND OF THE INVENTION

A variety of disorders in humans and other mammals involve or areassociated with abnormal bone resorption. Such disorders include, butare not limited to, osteoporosis, glucocorticoid induced osteoporosis,Paget's disease, abnormally increased bone turnover, periodontaldisease, tooth loss, bone fractures, rheumatoid arthritis,osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta,metastatic bone disease, hypercalcemia of malignancy, and multiplemyeloma. One of the most common of these disorders is osteoporosis,which in its most frequent manifestation occurs in postmenopausal women.Osteoporosis is a systemic skeletal disease characterized by a low bonemass and microarchitectural deterioration of bone tissue, with aconsequent increase in bone fragility and susceptibility to fracture.Osteoporotic fractures are a major cause of morbidity and mortality inthe elderly population. As many as 50% of women and a third of men willexperience an osteoporotic fracture. A large segment of the olderpopulation already has low bone density and a high risk of fractures.There is a significant need to both prevent and treat osteoporosis andother conditions associated with bone resorption. Because osteoporosis,as well as other disorders associated with bone loss, are generallychronic conditions, it is believed that appropriate therapy willtypically require chronic treatment.

Osteoporosis is characterized by progressive loss of bone architectureand mineralization leading to the loss in bone strength and an increasedfracture rate. The skeleton is constantly being remodeled by a balancebetween osteoblasts that lay down new bone and osteoclasts thatbreakdown, or resorb, bone. In some disease conditions and advancing agethe balance between bone formation and resorption is disrupted; bone isremoved at a faster rate. Such a prolonged imbalance of resorption overformation leads to weaker bone structure and a higher risk of fractures.

Bone resorption is primarily performed by osteoclasts, which aremultinuclear giant cells. Osteoclasts resorb bone by forming an initialcellular attachment to bone tissue, followed by the formation of anextracellular compartment or lacunae. The lacunae are maintained at alow pH by a proton-ATP pump. The acidified environment in the lacunaeallows for initial demineralization of bone followed by the degradationof bone proteins or collagen by proteases such as cysteine proteases.See Delaisse, J. M. et al., 1980, Biochem J 192:365-368; Delaisse, J. etal., 1984, Biochem Biophys Res Commun:441-447; Delaisse, J. M. etal.,1987, Bone 8:305-313, which are hereby incorporated by reference intheir entirety. Collagen constitutes 95% of the organic matrix of bone.Therefore, proteases involved in collagen degradation are an essentialcomponent of bone turnover, and as a consequence, the development andprogression of osteoporosis.

Cathepsins belong to the papain superfamily of cysteine proteases. Theseproteases function in the normal physiological as well as pathologicaldegradation of connective tissue. Cathepsins play a major role inintracellular protein degradation and turnover and remodeling. To date,a number of cathepsin have been identified and sequenced from a numberof sources. These cathepsins are naturally found in a wide variety oftissues. For example, cathepsin B, F, H, L, K, S, W, and Z have beencloned. Cathepsin K (which is also known by the abbreviation cat K) isalso known as cathepsin O and cathepsin O2. See PCT Application WO96/13523, Khepri Pharmaceuticals, Inc., published May 9, 1996, which ishereby incorporated by reference in its entirety. Cathepsin L isimplicated in normal lysosomal proteolysis as well as several diseasestates, including, but not limited to, metastasis of melanomas.Cathepsin S is implicated in Alzheimer's disease and certain autoimmunedisorders, including, but not limited to juvenile onset diabetes,multiple sclerosis, pemphigus vulgaris, Graves' disease, myastheniagravis, systemic lupus erythemotasus, rheumatoid arthritis andHashimoto's thyroiditis; allergic disorders, including, but not limitedto asthma; and allogenic immunbe responses, including, but not limitedto, rejection of organ transplants or tissue grafts. Increased CathepsinB levels and redistribution of the enzyme are found in tumors,suggesting a role in tumor invasion and matastasis. In addition,aberrant Cathpsin B activity is implicated in such disease states asrheumatoid arthritis, osteoarthritis, pneumocystisis carinii, acutepancreatitis, inflammatory airway disease and bone and joint disorders.

Cysteine protease inhibitors such as E-64(trans-epoxysuccinyl-L-leucylamide-(4-guanidino)butane) are known to beeffective in inhibiting bone resorption. See Delaisse, J. M. et al.,1987, Bone 8:305-313, which is hereby incorporated by reference in itsentirety. Recently, cathepsin K was cloned and found specificallyexpressed in osteoclasts See Tezuka, K. et al., 1994, J Biol Chem269:1106-1109; Shi, G. P. et al., 1995, FEBS Lett 357:129-134; Bromme,D. and Okamoto, K., 1995, Biol Chem Hoppe Seyler 376:379-384; Bromme, D.et al., 1996, J Biol Chzem 271:2126-2132; Drake, F. H. et al., 1996, JBiol Chem 271:12511-12516, which are hereby incorporated by reference intheir entirety. Concurrent to the cloning, the autosomal recessivedisorder, pycnodysostosis, characterized by an osteopetrotic phenotypewith a decrease in bone resorption, was mapped to mutations present inthe cathepsin K gene. To date, all mutations identified in the cathepsinK gene are known to result in inactive protein. See Gelb, B. D. et al.,1996, Science 273:1236-1238; Johnson, M. R. et aL, 1996, Genome Res6:1050-1055, which are hereby incorporated by reference in theirentirety. Therefore, it appears that cathepsin K is involved inosteoclast mediated bone resorption.

Cathepsin K is synthesized as a 37 kDa pre-pro enzyme, which islocalized to the lysosomal compartment and where it is presumablyautoactivated to the mature 27 kDa enzyme at low pH. See McQueney, M. S.et al., 1997, J Biol Chem 272:13955-13960; Littlewood-Evans, A. et al.,1997, Bone 20:81-86, which are hereby incorporated by reference in theirentirety. Cathepsin K is most closely related to cathepsin S having 56%sequence identity at the amino acid level. The S₂P₂ substratespecificity of cathepsin K is similar to that of cathepsin S with apreference in the P1 and P2 positions for a positively charged residuesuch as arginine, and a hydrophobic residue such as phenylalanine orleucine, respectively. See Bromme, D. et al., 1996, J Biol Chem 271:2126-2132; Bossard, M. J. et al., 1996, J Biol Chem 271:12517-12524,which are hereby incorporated by reference in their entirety. CathepsinK is active at a broad pH range with significant activity between pH4-8, thus allowing for good catalytic activity in the resorption lacunaeof osteoclasts where the pH is about 4-5.

Human type I collagen, the major collagen in bone is a good substratefor cathepsin K. See Kafienah, W., et al., 1998, Biochem J 331:727-732,which is hereby incorporated by reference in its entirety. In vitroexperiments using antisense oligonucleotides to cathepsin K, have showndiminished bone resorption in vitro, which is probably due to areduction in translation of cathepsin K mRNA. See Inui, T., et al.,1997, J Biol Chem 272:8109-8112, which is hereby incorporated byreference in its entirety. The crystal structure of cathepsin K has beenresolved. See McGrath, M. E., et al., 1997, Nat Struct Biol 4:105-109;Zhao, B., et al., 1997, Nat Struct Biol 4: 109-11, which are herebyincorporated by reference in their entirety. Also, selective peptidebased inhibitors of cathepsin K have been developed See Bromme, D., etal., 1996, Biochem J 315:85-89; Thompson, S. K., et al., 1997, Proc NatlAcad Sci U S A 94:14249-14254, which are hereby incorporated byreference in their entirety. Accordingly, inhibitors of Cathepsin K canreduce bone resorption. Such inhibitors would be useful in treatingdisorders involving bone resorption, such as osteoporosis.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are capable of treatingand/or preventing cathepsin dependent conditions or disease states in amammal in need thereof. One embodiment of the present invention isillustrated by a compound of Formula I, and the pharmaceuticallyacceptable salts, stereoisomers and N-oxide derivatives thereof:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the following chemicalformula:

wherein R¹ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyland alkenyl groups are optionally substituted with halo;

-   R² is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and    alkenyl groups are optionally substituted with halo;-   or R¹ and R² can be taken together with the carbon atom to which    they are attached to form a C₃₋₈ cycloalkyl ring wherein said ring    system is optionally substituted with C₁₋₆ alkyl, hydroxyalkyl or    halo;-   R³ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and    alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or    halo;-   R⁴ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and    alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or    halo;-   or R³ and R⁴ can be taken together with the carbon atom to which    they are attached to form a C₃₋₈ cycloalkyl ring, C₅₋₈ cycloalkenyl    ring, or five to seven membered heterocycloalkyl wherein said    cycloalkyl, cycloalkenyl and heterocycloalkyl groups are optionally    substituted with C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or    keto;-   X is selected from the group consisting of —O—, —S—, SO₂, and    —C(R⁵)(R⁶)—;-   R⁵ is hydrogen or C₁₋₆ alkyl;-   R⁶ is hydrogen or C₁₋₆ alkyl;-   or R⁵ and R⁶ can be taken together with any of the atoms to which    they may be attached or are between them to form a 3-8 membered    cycloalkyl ring system wherein said ring system is optionally    substituted with C₁₋₆ alkyl or halo;-   R⁷ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    haloalkyl, C₁₋₆ alkyloxy, nitro, cyano, aryl, heteroaryl, C₃₋₈    cycloalkyl, heterocycloalkyl, —C(O)OR¹⁰, —C(O)R¹⁰,    —C(O)OSi[CH(CH₃)₂]₃, —R¹⁰C(O)R¹³, —C(O)R¹³, —C(O)N(R¹²)(R¹²),    —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂,    —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹),    —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³),    —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b)),    —C(R^(a))(R^(b))N(R^(a))(R^(b)),    —(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)    R¹³ or C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said groups are    optionally substituted on either the carbon or the heteroatom with    one to five substituents independently selected from C₁₋₆ alkyl,    halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂,    —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², —SO(R¹²),    —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹),    —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)),    —N(R¹⁰)C(R¹⁰)(R¹¹)(R¹³), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃,    heterocycloalkl, aryl or heteroaryl;-   R⁸ is hydrogen, C₁₋₆ alky, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆    haloalkyl, C₁₋₆ alkyloxy, nitro, cyano, aryl, heteroaryl, C₃₋₈    cycloalkyl, heterocycloalkyl, —C(O)OR¹⁰, —C(O)R¹⁰,    C(O)OSi[CH(CH₃)₂]₃, —R¹⁰C(O)R¹³, —C(O)R¹³, —C(O)N(R¹²)(R¹²),    —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂,    —C(R¹⁰)(R¹¹)NR¹⁰C(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³,    —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³),    —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))(R¹³),    —C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)    R¹³ or C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said groups are    optionally substituted on either the carbon or the heteroatom with    one to five substituents independently selected from C₁₋₆ alkyl,    halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂,    —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², SO(R¹²),    —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹),    —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)),    —N(R¹⁰)C(R¹⁰)(R¹¹)(R¹³), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃,    heterocycloalky, aryl or heteroaryl;-   D is aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, C₁₋₃ alkyl    or C₁₋₃ alkenyl wherein said aryl, heteroaryl, cycloalkyl and    heterocycloalkyl groups, which may be monocyclic or bicyclic, are    optionally substituted on either the carbon or the heteroatom with    one to three substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₁₋₆ alkyloxy, halo, keto, nitro, cyano, aryl,    heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl, —C(O)OR¹⁰,    —C(O)OSi[CH(CH₃)₂]₃, —OR¹⁰, —C(O)R¹⁰, —R¹⁰C(O)R¹³, —C(O)R¹³,    —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —SR¹², —SR¹³, —R¹⁰SR¹³, —R¹³,    —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂, —SO₂R¹², —SO(R¹²), —SO₂R¹³,    —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹), —SO₂N(R¹⁰)C(O)(R¹²),    —SO₂(R¹⁰)C(O)N(R¹²)₂, —OSO₂R¹⁰, —N(R¹⁰)(R¹¹), —N(R¹⁰)C(O)NR¹⁰R¹³,    —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂R¹⁰,    —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³,    —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³), R¹⁰S—,    —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))(R¹³),    —C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R¹³    or —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said groups are    optionally substituted on either the carbon or the heteroatom with    one to five substituents independently selected from C₁₋₆ alkyl,    C₃₋₈ cycloalkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR¹³,    —NO₂, —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², —SO(R¹²),    —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹),    —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)),    —N(R¹⁰)C(R¹⁰)(R¹¹), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃,    heterocycloalkyl, aryl or heteroaryl;-   R⁹ is hydrogen, hydroxy, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆    alkynyl, C₁₋₆ alkyloxy, halo, aryl, heteroaryl, C₃₋₈ cycloalkyl,    heterocycloalkyl, —C(O)OR¹⁰, —OR¹⁰, —C(O)R¹⁰, —C(O)R¹³,    —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃,    —C(R¹⁰)(R¹¹)N(R¹³)₂, SR¹⁰, —SO₂R¹², —SO(R¹²), —SO₂R¹³,    —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹), —N(R¹⁰)(R¹¹),    —N(R¹⁰)C(O)NR¹⁰R¹³, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂R¹⁰,    —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³,    —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)—, R¹⁰S—,    —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b)),    —C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)),    —C(R^(a))(R^(b))N(R^(a))C(O)R¹³; wherein said groups are optionally    substituted on either the carbon or the heteroatom with one to five    substituents independently selected from C₁₋₆ alkyl, C₃₋₈    cycloalkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR¹³, —NO₂,    —NH₂, —NHS(O)₂R⁸, —R¹³SO₂R¹², SO₂R¹², SO(R¹²), SO₂N(R^(c))(R^(d)),    SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH,    —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹),    —NH(CH₂)₂OH, —NHC(O)OR¹⁰, Si(CH₃)₃, heterocycloalkyl, aryl or    heteroaryl;-   R¹⁰ is hydrogen or C₁₋₆ alkyl;-   R¹¹ is hydrogen or C₁₋₆ alkyl;-   R¹² is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo, alkoxy, cyano, —NR¹⁰ or —SR¹⁰;-   R¹³ is selected from the group consisting of hydrogen, aryl,    aryl(C₁₋₄) alkyl, heteroaryl, heteroaryl(C₁₋₄)alkyl, C₃₋₈cycloalkyl,    C₃₋₈cycloalkyl(C₁₋₄)alkyl, and heterocycloalkyl(C₁₋₄)alkyl wherein    said groups can be optionally substituted with halo or alkoxy;-   R^(a)is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆    alkyl)hydroxyl, —O(C₁₋₆ alkyl), hydroxyl, halo, aryl, heteroaryl,    C₃₋₈ cycloalkyl, heterocycloalkyl, wherein said alkyl, aryl,    heteroaryl, C₃₋₈ cycloalkyl and heterocycloalkyl can be optionally    substituted on either the carbon or the heteroatom with C₁₋₆ alkyl    or halo;    R^(b) is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆    alkyl)hydroxyl, alkoxyl, hydroxyl, halo, aryl, heteroaryl, C₃₋₈    cycloalkyl, heterocycloalkyl,wherein said alkyl, aryl, heteroaryl,    C₃₋₈ cycloalkyl and heterocycloalkyl can be optionally substituted    on either the carbon or the heteroatom with C₁₋₆ alkyl or halo;-   or R^(a) and R^(b) can be taken together with the carbon atom to    which they are attached or are between them to form a C₃₋₈    cycloalkyl ring or C₃₋₈ heterocycloalkyl ring wherein said 3-8    membered ring system may be optionally substituted with C₁₋₆ alkyl    and halo;-   R^(c) is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo or OR¹³;-   R^(d) is hydrogen or C₁₋₆ alkyl which is optionally substituted with    halo or OR¹³;-   or R^(c) and R^(d) can be taken together with the nitrogen atom to    which they are attached or are between them to form a C₃₋₈    heterocycloalkyl ring which is optionally substituted with C₁₋₆    alkyl, halo hydroxyalkyl, hydroxy, alkoxy or keto; n is zero, one,    two or three; and the pharmaceutically acceptable salts and N-oxide    derivatives thereof.

In an embodiment of the invention, R¹ and R² are each hydrogen. Inanother embodiment of the invention, R¹ and R², when on the same carbonatom, can be taken together with the carbon atom to which they areattached to form a 3-8 membered ring system wherein said ring system isoptionally substituted with C₁₋₆ alkyl, hydroxyalkyl or halo. Examplesof ring systems that can be formed include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. In a further embodiment, R¹ andR², when on the same carbon atom, can be taken together with the carbonatom to which they are attached to form a cyclopropyl ring wherein saidring system is optionally substituted with C₁₋₆ alkyl or halo. Apreferred embodiment is when cyclopropyl is formed.

In an embodiment of the invention, R³ is hydrogen and R⁴ are eachindependently C₁₋₆ alkyl which is optionally substituted with C₃₋₆cycloalkyl ring or halo. In a futher embodiment of the invention R³ ishydrogen and R⁴ is isobutyl. In another embodiment of the invention, R³and R⁴, when on the same carbon atom, can be taken together with thecarbon atom to which they are attached to form C₃₋₈ cycloalkyl ring,C₅₋₈ cycloalkenyl ring, or five to seven membered heterocyclyl whereinsaid cycloalkyl, cycloalkenyl and heterocyclyl groups are optionallysubstituted with C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, alkoxy orketo. Examples of ring systems that can be formed include, but are notlimited to the following, keeping in mind that the heterocycle isoptionally substituted with one or more substituents as described above:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Apreferred embodiment is when cyclohexyl is formed.

In an embodiment of the invention, X is —O—, —S— or —SO₂—. In a furtherembodiment of the invention, X is O.

In an embodiment of the invention, R⁷ is aryl, heteroaryl or C₁₋₆haloalkyl and R⁸ is hydrogen. In a further embodiment of the invention,R⁷ is phenyl or CF₃.

In an embodiment of the invention, D is aryl, heteroaryl, cycloalkyl orheterocycloalkyl. In a further embodiment of the invention, D is phenylor pyridyl.

In an embodiment of the invention, R⁹ is aryl, heteroaryl orheterocycloalkyl, wherein said groups are optionally substituted oneither the carbon or the heteroatom with one to five substituentsindependently selected from C₁₋₆ alkyl, halo, —SO₂R¹², —SO(R¹²) or aryl.In a further embodiment of the invention, R⁹ is piperidine,phenylpiperazine, pyridine or phenylmethylsulfone.

In an embodiment of the invention, R^(a) and R^(b) are defined such thatthey can be taken together with the carbon or nitrogen to which they areattached to form a monocyclic or bicyclic carbocycle or heterocycle with5-7 members in each ring. The heterocycle can optionally contain, inaddition to the nitrogen, 1 or 2 additional heteroatoms selected from N,O and S. Said carbocycle and heterocycle can be optionally substitutedwith one or more substituents selected from C₁₋₆ alkyl and halo.

Embodied by the present invention are methods for treating disordersrelated to abnormal bone resoprtion. Such disorders include, but are notlimited to, osteoporosis, glucocorticoid induced osteoporosis, Paget'sdisease, abnormally increased bone turnover, periodontal disease, toothloss, bone fractures, rheumatoid arthritis, osteoarthritis,periprosthetic osteolysis, osteogenesis imperfecta, metastatic bonedisease, hypercalcemia of malignancy, and multiple myeloma. A preferredembodiment includes methods for treating osteoporosis and metastaticbone disease. A more preferred embodiment includes methods for treatingosteoporosis.

Specific embodiments of the present invention include, but are notlimited to:

-   (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide;-   (2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-[4-(methylsulfonyl)phenyl](4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-[4′-(1H-imidazol-1-yl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}-4-methylpentanamide;-   (2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-(benzhydryloxy)-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-{[(S)-(4-chlorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpenteanamide;-   (2S)-N-(cyanomethyl)-2-{[(S)-mesityl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-4-methylpentanamide;-   1-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)cyclohexanecarboxade;-   (2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-{[(R)-(4-bromophenyl)(cyclopropyl)methyl]oxy}-N-(cyanomethyl)-4-methylpenteanamide;-   (2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methyipentanamide;-   2-[(4-bromophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[(4-bromophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[[4-(3-chloropyrazin-2-yl)phenyl](phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(1,3-thiazol-2-yl)phenyl]methoxy}pentanamide;-   (2S)-2-[[4′-(aminosulfonyl)-1,1′-biphenyl-4-yl](phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl](phenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-quinolin-3-ylphenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrimidin-5-ylphenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-quinohn-8-ylphenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-2-[{4-[6-(hydroxymethyl)-1-oxidopyridin-3-yl]phenyl}(phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-4-ylphenyl)methoxy]pentananide;-   (2S)-N-(cyanomethyl)-2-[[4-(1H-indol-4-yl)phenyl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-2-ylphenyl)methoxy]pentanamde;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrazin-2-ylphenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-3-ylphenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-(phenyl{4-[5-(2H-tetraazol-5-yl)pyridin-3-yl]phenyl}methoxy)pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[[4-(3-methylpyridin-2-yl)phenyl](phenyl)methoxy]pentanamide;-   2-{4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy]methylbutyl)oxy](phenyl)methyl]phenyl}isonicotinic    acid;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrmdin-2-ylphenyl)methoxy]pentanamide;-   ethyl    4′-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-carboxylate;-   4′-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-carboxamnide;-   N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide;-   N-(cyanomethyl)-2-[(4-{[4-(2-fluoroethyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-[(4-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]pentanamide;-   (2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(thien-2-yl)methyl]oxy}pentanamide;-   (2S)-2-[(4-bromophenyl)(thien-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanade;-   2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(pyridin-2-yl)methoxy]pentanamide;-   N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(1,3-thiazol-2-yl)methoxy]pentanamide;-   2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[1-(4-bromophenyl)ethoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[1-(4-bromophenyl)propoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[1-(4-bromophenyl)ethoxy]-N-(cyanomethyl)-4-methylpentanamide;-   N-(cyanomethyl)-2-[(4-fluorophenyl)(4-pyridin-4-ylphenyl)methoxy]-4-methylpentanamide;-   2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide;-   N-(cyanomethyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpenteanamide;-   2-[1-(4-bromophenyl)propoxy]-N-(cyanomethyl)-4-methylpentanamide;-   N-(1-cyanocyclopropyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpenteanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide;-   (2S)-2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}penteanamide;-   N-(cyanomethyl)-4-methyl-2-[1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide;-   N-(cyanomethyl)-4-methyl-2-[1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide;-   (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylthio)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}penteanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide;-   (2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-(4′-morpholin-4-yl-1,1′-biphenyl-4-yl)(phenyl)methyl]oxy}pentanamide;-   (2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamide;-   2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-(4-cyanophenyl)(phenyl)methyl]oxy}-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-(4-ethynylphenyl)(phenyl)methyl]oxy}-4-methylpentanamide;-   2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-[2,2,2-trifluoro-1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide;-   2-{[(S)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-4-ylphenyl)methoxy]pentanamide;-   N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide;-   (2R)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4′-[4-(methylsulfonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}(phenyl)methyl]oxylpentanamide;-   2-{[(4-bromophenyl)(phenyl)methyl]thio}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4′-(4-methylpiperazin-1-yl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide;-   N-(cyanomethyl)-4-methyl-2-(2,2,2-trifluoro-1-}4′-[4-(methylsulfonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}ethoxy)pentanamide;-   2-[(4-bromophenyl)(2,4,6-trifluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[bis(4-bromophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanamide;-   4-{4′-[(R)-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-yl}-1,1-dimethylpiperazin-1-ium    iodide;-   (2S)-N-(cyanomethyl)-2-{[(R)-{4′-[4-(2-hydroxyethyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}(phenyl)methyl]oxy}-4-methylpentanamide;-   2-{[(4-bromophenyl)(phenyl)methyl]sulfonyl}-N-(cyanomethyl)-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-{2,2,2-trifluoro-1-[4′-(methylthio)-1,1′-biphenyl-4-yl]ethoxy}pentanamide;-   2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide;-   N-(cyanomethyl)-4-methyl-2-{2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethoxy}pentanamide;-   4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy(phenyl)methyl]-N-methoxy-N-methylbenzamide;-   4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-N,N-dimethylbenzamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-[[4-(morpholin-4-ylcarbonyl)phenyl](phenyl)methoxy]pentanamide;-   4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoic    acid;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylthio)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylsulfonyl)benzoyl]phenyl}(phenyl)methyl]oxy}pentanaminde;-   (2S)-2-{[(R)-[4-(1,1′-biphenyl-4-ylcarbonyl)phenyl](phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[{5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[5-(4-piperazin-1-ylphenyl)pyridin-2-yl]methoxy}pentanamide;-   (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamide;-   (2S)-N-(cyanomethyl-4-methyl-2-{[R or    S)-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl-4-methyl-2-{[(R or    S)-{5-[4-methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2-yl}(phenyl)methoxy]pentananide;-   (2S)-2-[(4-bromothien-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-2-[(5-bromo-1-oxidopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy)-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methyl-1-oxidopyridin-3-yl)phenyl](phenyl)(phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-4-yl)henyl)(phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1-oxidopiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)-1-oxidopiperidin-4-yl]phenyl}(phenyl)(phenyl)methyl]oxy-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(5-methylcyclohex-1-en-1-yl)phenyl(phenyl)methyl]oxy}pentanamide;-   3-{4-[(R)-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]phenyl}-1-methylpyridinium    iodide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy)pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methylloxy}pentanamide;-   (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidoquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide;-   (2S)-N-(cyanomethyl)-2-[(R)-(4-[1-(2-methoxyethyl)-1-oxidopiperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(1-hydroxycyclopropyl)biphenyl-4-yl](phenyl)methoxyl-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-4-methyl-2-{(R)-phenyl[4′-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-4-yl]methoxy}pentanamide;-   (2S)-2-[(R)-[4′-(1-amino-2,2,2-trifluoroethyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide;-   1-{4′-[(R)-[((1S)-1-{[(1-cyanocyclopropyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]biphenyl-4-yl}cyclopropanecarboxylic    acid;-   2-{4′-[(R)-[((1S)-1-{[(1-cyanocyclopropyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]biphenyl-4-yl}-2-hydroxypropanoic    acid;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(2-hydroxyethyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-}4′-[cyclopropyl(hydroxy)methyl]biphenyl-4-yl}(phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1-hydroxyethyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1-hydroxy-1-methylethyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1-cyanocyclopropyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(1-cyanocyclopropyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide;-   (2S)-2-[(R)-[3′,4′-bis(1-hydroxy-1-methylethyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide;-   (2S)-2-[(R)-[3′,4′-bis(1-hydroxycyclopropyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide;-   and the pharmaceutically acceptable salts, stereoisomers and N-oxide    derivatives thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Theinvention is also contemplated to encompass a pharmaceutical compositionwhich is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. Theseand other aspects of the invention will be apparent from the teachingscontained herein.

Utilities

The compounds of the present invention are inhibitors of cathepsins andare therefore useful to treat or prevent cathepsin dependent diseases orconditions in mammals, preferably humans. Specifically, the compounds ofthe present invention are inhibitors of Cathepsin K and are thereforeuseful to treat or prevent Cathepsin K dependent diseases or conditionsin mammals, preferably humans.

“Cathepsin dependent diseases or conditions” refer to pathologicconditions that depend on the activity of one or more cathepsins.“Cathepsin K dependent diseases or conditions” refers to pathologicconditions that depend on the activity of Cathepsin K. Diseasesassociated with Cathepsin K activities include osteoporosis,glucocorticoid induced osteoporosis, Paget's disease, abnormallyincreased bone turnover, periodontal disease, tooth loss, bonefractures, rheumatoid arthritis, osteoarthritis, periprostheticosteolysis, osteogenesis imperfecta, metastatic bone disease,hypercalcemia of malignancy, and multiple myeloma. In treating suchconditions with the instantly claimed compounds, the requiredtherapeutic amount will vary according to the specific disease and isreadily ascertainable by those skilled in the art. Although bothtreatment and prevention are contemplated by the scope of the invention,the treatment of these conditions is the preferred use.

An embodiment of the invention is a method of inhibiting cathepsinactivity in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of any of the compounds or anyof the pharmaceutical compositions described above.

A class of the embodiment is the method wherein the cathepsin activityis cathepsin K activity.

Another embodiment of the invention is a method of treating orpreventing cathepsin dependent conditions in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above.

A class of the embodiment is the method wherein the cathepsin activityis cathepsin K activity.

Another embodiment of the invention is a method of inhibiting bone lossin a mammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above. Another embodiment of theinvention is a method of reducing bone loss in a mammal in need thereof,comprising administering to the mammal a therapeutically effectiveamount of any of the compounds or any of the pharmaceutical compositionsdescribed above. The utility of cathepsin K inhibitors in the inhibitionof bone resorption is known in the literature, see Stroup, G. B., Lark,M. W., Veber, D F., Bhattacharrya, A., Blake, S., Dare, L. C., Erhard,K. F., Hoffman, S. J., James, I. E., Marquis, R. w., Ru, Y.,Vasko-Moser, J. A., Smith, B. R., Tomaszek, T. and Gowen, M. Potent andselective inhibition of human cathepsin K leads to inhibition of boneresorption in vivo in a nonhuman primate. J. Bone Miner. Res.,16:1739-1746; 2001; and Votta, B. J., Levy, M. A., Badger, A., Dodds, R.A., James, I. E., Thompson, S., Bossard, M. J., Carr, T., Connor, J. R.,Tomaszek, T. A., Szewczuk, L., Drake, F. H., Veber, D., and Gowen, M.Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption bothin vivo and in vitro. J. Bone Miner. Res. 12:1396-1406; 1997.

Another embodiment of the invention is a method of treating orpreventing osteoporosis in a mammal in need thereof, comprisingadministering to the mammal a therapeutically effective amount of any ofthe compounds or any of the above pharmaceutical compositions describedabove. The utility of cathepsin K inhibitors in the treatment orprevention of osteoporosis is known in the literature, see Saftig, P.,Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W.,Moritz, J. D., Schu, P., and Vonfigura, K. Impaired osteoclast boneresorption leads to osteoporosis in cathepsin K-deficient mice. Proc.Natl. acad. Sci. USA 95:13453-13458; 1998.

Another embodiment of the invention is a method treating cancer in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of any of the compounds or any of thepharmaceutical compositions described above. It is known in theliterature that Cathepsin K is expressed in human breast carcinoma, seeLittlewood-Evans A J, Bilbe G, Bowler W B, Farley D, Wlodarski B, KokuboT, Inaoka T, Sloane J, Evans D B, Gallagher J A, “Theosteoclast-associated protease cathepsin K is expressed in human breastcarcinoma.”

Cancer Res December 1, 1997;57(23):5386-90.

Exemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of osteoporosis in a mammal in need thereof. Still furtherexemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of: bone loss, bone resorption, bone fractures, metastaticbone disease and/or disorders related to cathepsin functioning.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

In the case of tablets for oral use, carriers which are commonly usedinclude lactose and cornstarch, and lubricating agents, such asmagnesium stearate, are commonly added. For oral administration incapsule form, useful diluents include lactose and dried cornstarch. Fororal use of a therapeutic compound according to this invention, theselected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. For oraladministration in the form of a tablet or capsule, the active drugcomponent can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or betalactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

The instant compounds are also useful in combination with known agentsuseful for treating or preventing osteoporosis, glucocorticoid inducedosteoporosis, Paget's disease, abnormally increased bone turnover,periodontal disease, tooth loss, bone fractures, rheumatoid artritis,osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta,metastatic bone disease, hypercalcemia of malignancy, and multiplemyeloma. Combinations of the presently disclosed compounds with otheragents useful in treating or preventing osteoporosis or other bonedisorders are within the scope of the invention. A person of ordinaryskill in the art would be able to discern which combinations of agentswould be useful based on the particular characteristics of the drugs andthe disease involved. Such agents include the following: an organicbisphosphonate; an estrogen receptor modulator; an androgen receptormodulator; an inhibitor of osteoclast proton ATPase; an inhibitor ofHMG-CoA reductase; an integrin receptor antagonist; an osteoblastanabolic agent, such as PTH; and the pharmaceutically acceptable saltsand mixtures thereof. A preferred combination is a compound of thepresent invention and an organic bisphosphonate. Another preferredcombination is a compound of the present invention and an estrogenreceptor modulator. Another preferred combination is a compound of thepresent invention and an androgen receptor modulator. Another preferredcombination is a compound of the present invention and an osteoblastanabolic agent.

“Organic bisphosphonate” includes, but is not limited to, compounds ofthe chemical formula

wherein n is an integer from 0 to 7 and wherein A and X areindependently selected from the group consisting of H, OH, halogen, NH₂,SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, bicyclic ringstructure containing two or three N, C1-C30 substituted alkyl, C1-C10alkyl substituted NH₂, C3-C10 branched or cycloalkyl substituted NH₂,C1-C10 dialkyl substituted NH₂, C1-C10 alkoxy, C1-C10 alkyl substitutedthio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl,pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, andbenzyl, such that both A and X are not selected from H or OH when n is0; or A and X are taken together with the carbon atom or atoms to whichthey are attached to form a C3-C10 ring.

In the foregoing chemical formula, the alkyl groups can be straight,branched, or cyclic, provided sufficient atoms are selected for thechemical formula. The C1-C30 substituted alkyl can include a widevariety of substituents, nonlimiting examples which include thoseselected from the group consisting of phenyl, pyridyl, furanyl,pyrrolidinyl, imidazonyl, NH₂, C1-C10 alkyl or dialkyl substituted NH₂,OH, SH, and C1-C10 alkoxy.

The foregoing chemical formula is also intended to encompass complexcarbocyclic, aromatic and hetero atom structures for the A and/or Xsubstituents, nonlimiting examples of which include naphthyl, quinolyl,isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonatesare also useful herein. Non-limiting examples of salts include thoseselected from the group consisting of aiLli metal, alkaline metal,ammonium, and mono-, di-, tri-, or tetra-C1-C30-alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts. Morepreferred are sodium salts. Non-limiting examples of derivatives includethose selected from the group consisting of esters, hydrates, andamides.

It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.Because of the mixed nomenclature currently in use by those of ordinaryskill in the art, reference to a specific weight or percentage of abisphosphonate compound in the present invention is on an acid activeweight basis, unless indicated otherwise herein. For example, the phrase“about 5 mg of a bone resorption inhibiting bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof, on an alendronic acid active weightbasis” means that the amount of the bisphosphonate compound selected iscalculated based on 5 mg of alendronic acid.

Non-limiting examples of bisphosphonates useful herein include thefollowing:

Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

Alendronate (also known as alendronate sodium or alendronate monosodiumtrihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidmonosodium trihydrate.

Alendronic acid and alendronate are described in U.S. Pat. No.4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No.5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No.5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No.5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which areincorporated by reference herein in their entirety.

Cycloheptylaminomethylene-1,1-bisphosphonic acid, Y M 175, Yamanouchi(incadronate, formerly known as cimadronate), as described in U.S. Pat.No. 4,970,335, to Isomura et al., issued Nov. 13, 1990, which isincorporated by reference herein in its entirety.

1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and thedisodium salt (clodronate, Procter and Gamble), are described in BelgiumPatent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of whichare incorporated by reference herein in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid(EB-1053).

1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,also known as BM-210955, Boehringer-Mannheim (ibandronate), is describedin U.S. Pat. No. 4,927,814, issued May 22, 1990, which is incorporatedby reference herein in its entirety.

1-hydroxy-2-imidazo-(1,2-a)pyridin-3-yethylidene (minodronate).

6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid(olpadronate).

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).

[2-(2-pyridinyl)ethylidene-1,1-bisphosphonic acid (piridronate) isdescribed in U.S. Pat. No. 4,761,406, which is incorporated by referencein its entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate).

(4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) asdescribed in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989,which is incorporated by reference herein in its entirety.

1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid(zoledronate).

Nonlimiting examples of bisphosphonates include alendronate,cimadronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, and zolendronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially a sodium, potassium, calcium,magnesium or ammonium salt of alendronic acid. Exemplifying thepreferred bisphosphonate is a sodium salt of alendronic acid, especiallya hydrated sodium salt of alendronic acid. The salt can be hydrated witha whole number of moles of water or non whole numbers of moles of water.Further exemplifying the preferred bisphosphonate is a hydrated sodiumsalt of alendronic acid, especially when the hydrated salt isalendronate monosodium trihydrate.

It is recognized that mixtures of two or more of the bisphosphonateactives can be utilized.

The precise dosage of the organic bisphosphonate will vary with thedosing schedule, the particular bisphosphonate chosen, the age, size,sex and condition of the mammal or human, the nature and severity of thedisorder to be treated, and other relevant medical and physical factors.Thus, a precise pharmaceutically effective amount cannot be specified inadvance and can be readily determined by the caregiver or clinician.Appropriate amounts can be determined by routine experimentation fromanimal models and human clinical studies. Generally, an appropriateamount of bisphosphonate is chosen to obtain a bone resorptioninhibiting effect, i.e. a bone resorption inhibiting amount of thebisphosphonate is administered. For humans, an effective oral dose ofbisphosphonate is typically from about 1.5 to about 6000 μg/kg bodyweight and preferably about 10 to about 2000 μg/kg of body weight. Foralendronate monosodium trihydrate, common human doses which areadministered are generally in the range of about 2 mg/day to about 40mg/day, preferably about 5 mg/day to about 40 mg/day. In the U.S.presently approved dosages for alendronate monosodium trihydrate are 5mg/day for preventing osteoporosis, 10 mg/day for treating osteoporosis,and 40 mg/day for treating Paget's disease.

In alternative dosing regimens, the bisphosphonate can be administeredat intervals other than daily, for example once-weekly dosing,twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In aonce weekly dosing regimen, alendronate monosodium trihydrate would beadministered at dosages of 35 mg/week or 70 mg/week.

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, estrogen, progestogen, estradiol, droloxifene, raloxifene,lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl[-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“An inhibitor of osteoclast proton ATPase”0 refers to an inhibitor ofthe proton ATPase, which is found on the apical membrane of theosteoclast, and has been reported to play a significant role in the boneresorption process. This proton pump represents an attractive target forthe design of inhibitors of bone resorption which are potentially usefulfor the treatment and prevention of osteoporosis and related metabolicdiseases. See C. Farina et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone antiresorptive agents,” DDT, 4:163-172 (1999)), which is hereby incorporated by reference in itsentirety.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for EMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165,4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin(LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

As used above, “integrin receptor antagonists” refers to compounds whichselectively antagonize, inhibit or counteract binding of a physiologicalligand to the α_(v)β₃ integrin, to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe αvβ5 integrin, to compounds which antagonize, inhibit or counteractbinding of a physiological ligand to both the α_(v)β₃ integrin and theα_(v)β₅ integrin, and to compounds which antagonize, inhibit orcounteract the activity of the particular integrin(s) expressed oncapillary endothelial cells. The term also refers to antagonists of theα_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The termalso refers to antagonists of any combination of α_(v)β₃, α_(v)β₅,α_(v)β₆, α_(v)β⁸, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. H. N. Lodeand coworkers in PNAS USA 96: 1591-1596 (1999) have observed synergisticeffects between an antiangiogenic αv integrin antagonist and atumor-specific antibody-cytokine (interleukin-2) fusion protein in theeradication of spontaneous tumor metastases. Their results suggestedthis combination as having potential for the treatment of cancer andmetastatic tumor growth. α_(v)β₃ integrin receptor antagonists inhibitbone resorption through a new mechanism distinct from that of allcurrently available drugs. Integrins are heterodimeric transmembraneadhesion receptors that mediate cell-cell and cell-matrix interactions.The α and β integrin subunits interact non-covalently and bindextracellular matrix ligands in a divalent cation-dependent manner. Themost abundant integrin on osteoclasts is α_(v)β₃ (>10⁷/osteoclast),which appears to play a rate-limiting role in cytoskeletal organizationimportant for cell migration and polarization. The α_(v)β₃ antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of macular degeneration, inhibition of arthritis,and inhibition of cancer and metastatic growth.

“An osteoblast anabolic agent” refers to agents that build bone, such asPTH. The intermittent administration of parathyroid hormone (PTH) or itsamino-terminal fragments and analogues have been shown to prevent,arrest, partially reverse bone loss and stimulate bone formation inanimals and humans. For a discussion refer to D. W. Dempster et al.,“Anabolic actions of parathyroid hormone on bone,” Endocr Rev 14:690-709 (1993). Studies have demonstrated the clinical benefits ofparathyroid hormone in stimulating bone formation and thereby increasingbone mass and strength. Results were reported by R M Neer et al., in NewEng J Med 344 1434-1441 (2001).

In addition, parathyroid hormone-related protein fragments or analogues,such as PTHrP-(1-36) have demonstrated potent anticalciuric effects [seeM. A. Syed et al., “Parathyroid hormone-related protein-(1-36)stimulates renal tubular calcium reabsorption in normal humanvolunteers: implications for the pathogenesis of humoral hypercalcemiaof malignancy,” JCEM 86: 1525-1531 (2001)] and may also have potentialas anabolic agents for treating osteoporosis.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents. The present inventionincludes within its scope prodrugs of the compounds of this invention.In general, such prodrugs will be functional derivatives of thecompounds of this invention which are readily convertible in vivo intothe required compound. Thus, in the methods of treatment of the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985, which is incorporated byreference herein in its entirety. Metabolites of these compounds includeactive species produced upon introduction of compounds of this inventioninto the biological milieu.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The terms “treating” or “treatment” of a disease as used hereinincludes: preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease; inhibiting the disease, i.e., arresting orreducing the development of the disease or its clinical symptoms; orrelieving the disease, i.e., causing regression of the disease or itsclinical symptoms.

The term “bone resorption,” as used herein, refers to the process bywhich osteoclasts degrade bone.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of osteoporosis or other bone disorders,comprising the administration of a therapeutically effective amount ofthe compounds of this invention, with or without pharmaceuticallyacceptable carriers or diluents. Suitable compositions of this inventioninclude aqueous solutions comprising compounds of this invention andpharmacologically acceptable carriers, e.g., saline, at a pH level,e.g., 7.4. The solutions may be introduced into a patient's bloodstreamby local bolus injection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for a cathepsin dependentcondition. Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittant throughout the dosage regimen.

The compounds of the present invention can be used in combination withother agents useful for treating cathepsin-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating cathepsin-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The scope of the invetion therefore encompasses the use of the instantlyclaimed compounds in combination with a second agent selected from: anorganic bisphosphonate; an estrogen receptor modulator; an androgenreceptor modulator; an inhibitor of osteoclast proton ATPase; aninhibitor of HMG-CoA reductase; an integrin receptor antagonist; anosteoblast anabolic agent, such as PTH; and the pharmaceuticallyacceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from theteachings contained herein.

Definitions

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

When any variable (e.g. R¹, R², R^(a)etc.) occurs more than one time inany constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare perrnissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the substitutable ring carbonatoms. If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear, branched, or cyclic arrangement. For example,“C₁-C₁₀ alkyl” specifically includes methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. “Alkoxy”represents an alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge.

The term “cycloalkyl” or “carbocycle” shall mean cyclic rings of alkanesof three to eight total carbon atoms, or any number within this range(i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl).

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight or branched, containingfrom 2 to 10 carbon atoms and at least 1 carbon to carbon double bond.Preferably 1 carbon to carbon double bond is present, and up to 4non-aromatic carbon-carbon double bonds may be present. Thus, “C₂-C₆alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms.Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. Asdescribed above with respect to alkyl, the straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “cycloalkenyl” shall mean cyclic rings of 3 to 10 carbon atomsand at least 1 carbon to carbon double bond (i.e., cycloprenpyl,cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl orcycloocentyl).

The term “alkynyl” refers to a hydrocarbon radical straight or branched,containing from 2 to 10 carbon atoms and at least 1 carbon to carbontriple bond. Up to 3 carbon-carbon triple bonds may be present. Thus,“C₂-C₆ alkynyl” means an alkynyl radical having from 2 to 6 carbonatoms. Alkynyl groups include ethynyl, propynyl and butynyl. Asdescribed above with respect to alkyl, the straight, branched or cyclicportion of the alkynyl group may contain triple bonds and may besubstituted if a substituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃) CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 10 atoms in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl oracenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring.

The term “heteroaryl”, as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein atleast one ring is aromatic and contains from 1 to 4 heteroatoms selectedfrom the group consisting of O, N and S. Heteroaryl groups within thescope of this definition include but are not limited to:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl,thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl,hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl,carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl,furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetra-hydroquinoline. In cases where theheteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively. Ifthe heteroaryl contains nitrogen atoms, it is understood that thecorresponding N-oxides thereof are also encompassed by this definition.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo. The term“keto” means carbonyl (C═O). The term “alkoxy” as used herein means analkyl portion, where alkyl is as defined above, connected to theremainder of the molecule via an oxygen atom. Examples of alkoxy includemethoxy, ethoxy and the like.

The term “haloalkyl” includes an alkyl portion, where alkyl is asdefined above, which is substituted with one to five halo.

The term “hydroxyalkyl” means a linear monovalent hydrocarbon raidcal ofone to six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one or two hydroxy groups,provided that if two hydroxy groups are present they are not both on thesame carbon atom. Representative examples include, but are not limitedto, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, andthe like.

The term “heterocycloalkye” or “heterocycle” as used herein is intendedto mean a 5- to 10-membered nonaromatic ring containing from 1 to 4heteroatoms selected from the group consisting of O, N and S, andincludes bicyclic groups. “Heterocycloalkyl” therefore includes, but isnot limited to the following: imidazolyl, piperazinyl, piperidinyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,dihydropiperidinyl, tetrahydrothiophenyl and the like. If theheterocycle contains a nitrogen, it is understood that the correspondingN-oxides thereof are also emcompassed by this definition.

The present invention also includes N-oxide derivatives andprotectedderivatives of compounds of Formula I. For example, whencompounds of Formula I contain an oxidizable nitrogen atom, the nitrogenatom can beconverted to an N-oxide by methods well known in the art.Also whencompounds of Formula I contain groups such as hydroxy, carboxy,thiol or anygroup containing a nitrogen atom(s), these groups can beprotected with asuitable protecting groups. A comprehensive list ofsuitable protectivegroups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula I can be prepared bymethods well known in the art.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocycloalkyl substituents may be unsubstituted or unsubstituted,unless specifically defined otherwise. For example, a (C₁-C₆) alkyl maybe substituted with one or more substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocycloalkyl, such as morpholinyl,piperidinyl, and so on. In the case of a disubstituted alkyl, forinstance, wherein the substituents are oxo and OH, the following areincluded in the definition: —(C═O)CH₂CH(OH)CH₃, —(C═O)OH,—CH₂(OH)CH₂CH(O), and so on.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., aryl C₀₋₈ alkyl) it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed inorganic or organic acids. For example,conventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like, as well as salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like. The preparation of the pharmaceuticallyacceptable salts described above and other typical pharmaceuticallyacceptable salts is more fully described by Berg et al., “PharmaceuticalSalts,” J. Pharmn. Sci, 1977:66:1-19, hereby incorporated by reference.The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

For purposes of this specification, the following abbreviations have theindicated meanings: AcOH = acetic acid Boc = t-butyloxycarbonyl Boc₂O =di-tert-butyl dicarbonate BuLi = butyl lithium CCl₄ = carbontetrachloride CH₂Cl₂ = methylene chloride CH₃CN = acetonitrile CHCl₃ =chloroform Cs₂CO₃ = cesium carbonate CuI = copper iodide DMA =N,N-dimethyl acetamide DMAP = 4-(dimethylamino)pyridine DMF =N,N-dimethylformamide DMSO = dimethylsulfoxide EDCI =1-(3-dimethylaminopropyl)-3- ethylcarbodiimidehydrochloride Et₂O =diethyl ether Et₃N = triethylamine EtOAc = ethyl acetate EtOH = ethanolHATU = o-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HOAc = acetic acid K₂CO₃ = potassium carbonateKOBu^(t) = potassium tert-butoxide LiOH = lithium hydroxide mCPBA =metachloroperbenzoic acid MeOH = methanol MeSO₃H = methane sulfonic acidMgSO₄ = magnesium sulfate Ms = methanesulfonyl = mesyl MsCl =methanesulfonyl chloride NaBH₄ = sodium borohydride NaH = sodium hydrideNa₂CO₃ = sodium carbonate NaHCO₃ = sodium hydrogencarbonate NaOH =sodium hydroxide Na₂SO₄ = sodium sulfate NBS = N-bromosuccinimide NH₃ =ammonia NH₄Cl = ammonium chloride Pd/C = palladium on carbon PdCl₂(dppf)= [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) Pd₂(dba)₃= tris(dibenzylideneacetone)dipalladium(0) PPh₃ = triphenylphosphinePPTS = pyridinium p-toluenesulfonate iPr₂Nli = lithium diisopropyl amidePyBOP = benzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexafluorophosphate rt = room temperature sat. aq. =saturated aqueous TFA = trifluoroacetic acid THF = tetrahydrofuran tlc =thin layer chromatography Me = methyl Et = ethyl n-Pr = normal propyli-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butyl

The novel compounds of the present invention can be prepared accordingto the following general procedures using appropriate materials and arefurther exemplified by the following specific examples. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The followingexamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare these compounds.All temperatures are degrees Celsius unless otherwise noted.

Compounds of the present invention can be prepared according to Scheme1, as indicated below. Thus an alpha-hydroxy acid can be condensed withan aldehyde, for example, upon azeotropic removal of water in thepresence of an acid. The dioxolone affords mainly the acid when treatedwith zinc chloride followed by a Grignard reagent at low temperature.The acid undergoes amide formation in the presence of a dehydratingagent like HATU. The left hand portion of the molecule is oftenderivatized using palladium-mediated reactions, such as a Suzukireaction. The product can be further modified to introduce otherpharmacophores.

Compounds of the present invention can also be prepared according toScheme 2, as indicated below. Alcohols can be derivatized to make thecorresponding tricholoacethimdate with a catalytic amount of sodiumhydride in ether provided that the reaction is quite concentrated. Inparallel, an alpha-hydroxy acid undergoes amide formation in thepresence of a dehydrating agent like HATU. The hydroxynitrile thusobtained can be reacted with a trichloroacetimidate in the presence ofacid to afford the ether product, which can then be further derivatizedto introduce other pharmacophores.

Compounds of the present invention can also be prepared according toScheme 3, as indicated below. Ketones and aldehydes can be reacted withhydrides, Grignard reagents or organolithium reagents to providealcohols that can be alkylated with an alpha bromo ester in the presenceof sodium hydride in DM. The ester can be hydrolyzed under aqueousconditions or under anhydrous conditions. After amide formation with adehydrating agent, the molecule can be further modified to introduceother pharmacophores.

As shown in scheme 4, sulfur derivatives comprised in the presentinvention have been prepared from the starting bromide corresponding toalcohols shown below. Triisopropylsilanethiol is a convenient source ofsulfur and it may be used in a sequential one-pot double nucleophilicdisplacement to give the thioether. The ester functionality issaponified and the resulting acid can be coupled in the usual fashionwith HATU to afford the amide. The molecule can be further modified tointroduce other pharmacophores. Oxidation of the sulfur atom to a higheroxidation state can be performed before or after introduction of thepharmacophores, depending on the functionality introduced.

EXAMPLE 1 Synthesis of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1 (5S)-2-(4-bromophenvl)-5-isobutyl-1,3-dioxolan-4-one

(2S)-2-hydroxy-4-methylpentanoic acid (46.4 g, 351 mmol) and4-bromobenzaldehyde (50 g, 270.2 mmol) were dissolved in 400 ml tolueneand pyridinium 4-methylbenzenesulfonate (340 mg, 1.35 inmol) was added.The mixture was refluxed in a Dean-Stark for 24 hours. The mixture wascooled, poured into 500 ml NaHCO₃(sat) and 500 ether, the phases wereseparated and the organic phase washed with 500 ml NaHCO₃(sat.) andbrine. The organic phase was dried with Na₂SO₄ and the solvent striped.400 ml Hexane was added to the resulting solid and the mixture wasstirred 1 hour in salt ice bath. The solution was filtered thru Celite,and the solvent removed.(5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture ofcis/trans) was obtained.

Step 2 (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoicacid

Zinc chloride (1.12 l of 1M solution in ether, 1120 mmol) was added to500 ml ether at −40° C.(5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture ofcis/trans) (56 g, 187 mmol) was then added dropwise in 200 ml ether(over 15 min), followed by phenylmagnesium bromide (125 ml of a 3Msolution in ether, 374 mmol) (dropwise over 45 min). The solution wasstirred at 0° C. for 2 hours. The reaction was quenched at 0° C. with800 ml of a saturated solution of NH₄Cl, the phases were separated andthe aqueous layer extracted with 800 ml ether. The organic layers werecombined, washed with brine, dried with MgSO₄ and the solvent wasremoved.(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid(de=86%) was obtained after purification on silica gel (5%ethylacetate/toluene).

Step 3(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid(46.5 g, 123 mmol) was dissolved in DMF (200 mL). To this mixture wasadded HATU (56.7 g, 149 mmol, 1.2 eg), Et₃N (57.7 g, 570 mmol, 4.6 eg),then added at 0° C. aminoacetonitrile hydrochloride (13.5 g, 146 mmol,1.19 eg). The resulting reaction mixture was stirred at room temperaturefor 3 hours; then poured into 1 L of half saturated sodium bicarbonate.The aqueous phase was extracted with EtOAc (2×500 mnL). Organic fractionwas washed with brine (200 mnL), IN HCl (200 mL), brine (200 mL), 0.5 NNaOH (300 mL), brine (200 mL). Solvent was evaporated under reducedpressure and the resulting dark red oil which was chromatographed with20% EA/hexane to give the title compound.

MS (−APCI): 413.0 [M−1]⁻

EXAMPLE 2 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide

(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide(1 g, 2.41 mmol) 1-[4-(dihydroxyboryl)phenyl]piperazin-4-ium chloride(642 mg, 2.65 mmol), PdCl₂(dppf) (88 mg, 0.120 mmol) and 2M Na₂CO₃ (4.8ml, 9.63 mmol) were dissolved in 25 ml DMF, the solution was degassed 3times and heated for 10 h @ 85° C. The solution was cooled, poured into125 ml NaHCO₃ (sat.) and the product extracted with 3×25 ml ethylacetate. The combined organic layers were then washed with 4× water,then dried with Na₂SO₄. The product was then purified on silica gel (5%MeOH/5%NH4OH/90% DCM).

MS (−APCI): 495.3 [M−1]⁻

EXAMPLE 3 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamideStep 1 4-(4-bromophenyl)pyridine

Pyridin-4-ylboronic acid (500 mg, 4.07 mmol), 1-bromo-4-iodobenzene(1.27 g, 4.47 mmol) and 2M Na₂CO₃ (6.1 ml, 12.2 mmol) were dissolved in20 ml DMF and the solution was degassed 3 times. PdCl₂(dppf) (149 mg,0.203 mnmol) was added and the mixture was stirred overnight at 80° C.The solution was cooled, poured into 100 ml NaHCO₃ (sat.) and extracted3 times with 20 ml ethyl acetate. The combined organic layers were thenwashed with 4× water, then dried with Na₂SO₄. 4-(4-bromophenyl)pyridinewas obtained and used without further purification.

Step 2(2S)-N-(cyanomethyl)-4-methyl-2-({(R)-phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)pentanamide

(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamidefrom Example 1 (692 mg, 1.67 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (444 mg, 1.75mmol), KOAc (492 mg, 5.01 mmol) and PdCl₂(dppf) were dissolved in 8 mlDMF. The solution was degassed 3 times and heated to 80° C. overnight.The solution was cooled, poured into 40 ml brine and the productextracted with 3×5 ml ethyl acetate. The combined organic layers werethen washed with 4× water, then dried with Na₂SO₄.(2S)-N-(cyanomethyl)-4-methyl-2-({(R)-phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyllmethyl}oxy)pentanamidewas obtained after purification on silica gel (40% ethylacetate/hexanes).

Step 3(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxyl}pentanamide

(2S)-N-(cyanomethyl)-4-methyl-2-({(R)-phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)pentanamide(100 mg, 0.216 mmol), 4-(4-bromophenyl)pyridine (56 mg, 0.238 mmol) and2M K₂CO₃ (324 ul, 0.648 mmol) were dissolved in 1.6 ml DMF and thesolution was degassed 3 times. PdCl₂(dppf) (4.8 mg, 0.03 mmol) was addedand the mixture was stirred overnight at 80° C. The solution was cooled,poured into 8 ml NaHCO₃ (sat.) and extracted 3 times with 2 ml ethylacetate. The combined organic layers were then washed with 4× water,then dried with Na₂SO₄.(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamidewas obtained after purification on silica gel (2%MeOH/38% ethylacetate/60% hexanes).

MS (+APCI): 490.3 [M+1]⁺

EXAMPLE 4 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-[4′-(1H-imidazol-1-yl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}-4-methylpentanamide

Following Step 3 of Example 3, the title compound was synthesized using1-(4-bromophenyl)-1H-imidazole instead of 4-(4-bromophenyl)pyridine.

MS (+APCI): 479.1 [M+1]⁺

EXAMPLE 5 Synthesis of(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-N-(cyanomethyl)-4-methylpentanamideStep 1(2S)-2-({(R)-(4-bromophenyl)[4-(methylthio)phenyl]methyl}oxy)-4-methylpentanoicacid

Following Step 2 of Example 1, the title compound was synthesized usingbromo[4-(methylthio)phenyl]magnesium instead of phenylmagnesium bromide.

Step 2(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-4-methylpentanoicacid

(2S)-2-({(R)-(4-bromophenyl)[4-(methylthio)phenyl]methyl}oxy)-4-methylpentanoicacid (103 mg, 0.243 mmol) (from Step 1) was dissolved in 2.5 ml DCM at0° C. and mCPBA (55-86%) (84 mg) was added, the solution was stirred for1 hour and an additional 42 mg of mCPBA was added. After stirring for 1hour the solvent was stripped and(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-4-methylpentanoicacid was obtained after purification on silica gel (1% AcOH/39% ethylacetate/60% Hexanes).

Step 3(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-4-methylpentanoicacid (from Step 2) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 491.2 [M−1]⁻

EXAMPLE 6 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-[4-(methylsulfonyl)phenyl](4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide

Following Step 1 of Example 2, the title compound was synthesized using(2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-N-(cyanomethyl)-4-methylpentanamideinstead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide.

MS (+APCI): 575.3 [M+1]⁺

EXAMPLE 7 Synthesis of(2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1(2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-4-methylpentanoicacid

Following Step 2 of Example 1, the title compound was synthesized usingbromo(4-chlorophenyl)magnesium instead of phenylmagnesium bromide.

Step 2(2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-4-methylpentanoicacid (from Step 1) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 447.0 [M−1]⁻

EXAMPLE 8 Synthesis of(2S)-2-{[(S)-(4-chlorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 1 of Example 2, the title compound was synthesized using(2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideinstead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide.

MS (+APCI): 531.2 [M+1]⁺

EXAMPLE 9 Synthesis of(2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1(2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-4-methylpentanoic acid

Following Step 2 of Example 1, the title compound was synthesized usingbromo(mesityl)magnesium instead of phenylmagnesium bromide.

Step 2(2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-4-methylpentanoic acid(from Step 1) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 455.1 [M−1]⁻

EXAMPLE 10(2S)-N-(cyanomethyl)-2-{[(S)-mesityl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-4-methylpentanamide

Following Step 1 of Example 2, the title compound was synthesized using(2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideinstead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide.

MS (+APCI): 539.4 [M+1]⁺

EXAMPLE 11 Preparation of(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(caanomethyl)-4-methylpentanamideStep 1(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-4-methylpentanoicacid

Following Step 2 of Example 1, the title compound was synthesized usingbromo(4-chlorobenzyl)magnesium is used instead of phenylmagnesiumbromide.

Step 2(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-4-methylpentanoicacid (from Step 1) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 461.2 [M−1]⁻

EXAMPLE 12 Preparation of(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1(2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 2 of Example 1, the title compound was synthesized usingbromo(cyclopropylmethyl)magnesium instead of phenylmagnesium bromide.

Step 2(2S)-2-}[(R)-(4-bromophenyl)(cyclopropyl)methyl]oxy}-4-methylpentanoicacid

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-{[(R)-(4-bromophenyl)(cyclopropyl)methyl]oxyl}-4-methylpentanoicacid (from Step 1) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 477.2 [M−1]⁻

EXAMPLE 13 Synthesis of(2S)-2-(benzhydryloxy)-N-(cyanomethyl)-4-methylpentanamide Step 1(5S)-5-isobutyl-2-phenyl-1,3-dioxolan-4-one

Following Step 1 of Example 1, the title compound was synthesized usingbenzaldehyde instead of 4-bromobenzaldyde.

Step 2 (2S)-2-(benzhvdryloxy)-4-methylpentanoic acid

Following Step 2 of Example 1, the title compound was synthesized using(5S)-5-isobutyl-2-phenyl-1,3-dioxolan-4-one instead of(5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one.

Step 3 (2S)-2-(benzhydryloxy)-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized(2S)-2-(benzhydryloxy)-4-methylpentanoic acid (from Step 2) was usedinstead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 335.1 [M−1]⁻

EXAMPLE 14 Synthesis of(2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1 (5S)-2-(3-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one

Following Step 1 of Example 1, the title compound was synthesized using3-bromobenzaldehyde bromobenzaldehyde instead of 4-bromobenzaldyde.

Step 2 (2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoicacid

Following Step 2 of Example 1, the title compound was synthesized using(5S)-2-(3-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (from Step 1)instead of (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one.

Step 3(2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Following Step 3 of Example 1, the title compound was synthesized using(2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid(from Step 2) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxyl}-4-methylpentanoic acid.

MS (−APCI): 413.1 [M−1]⁻

EXAMPLE 15 Synthesis of1-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)cyclohexanecarboxamideStep 1 2-(4-bromophenyl)-1,3-dioxaspiro[4,5]decan-4-one

Following Step 1 of Example 1, the title compound was synthesized using1-hydroxycyclohexanecarboxylic acid is used instead of(2S)-2-hydroxy-4-methylpentanoic acid.

Step 2 1-[(4-bromophenyl)(phenyl)methoxy]cyclohexanecarboxylic acid

Following Step 2 of Example 1, the title compound was synthesized using2-(4-bromophenyl)-1,3-dioxaspiro[4.5]decan-4-one (from Step 1) was usedinstead of (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one.

Step 31-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)cyclohexanecarboxamide

Following Step 3 of Example 1, the title compound was synthesized using1-[(4-bromophenyl)(phenyl)methoxy]cyclohexanecarboxylic acid (from Step2) instead of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid.

MS (−APCI): 425.1 [M−1]⁻

EXAMPLE 16 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pentanamide

To a solution of(2S)-2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamidefrom Example 1 (1 eq.), Bis(pinacolato)diboron (1.3 eq.) and potassiumacetate (4 eq.) in DMF (0.2M) was added PdCl₂(dppf) dichloromethanecomplex. The solution was briefly degassed by bubbling nitrogen throughthe solution and the mixture was heated at 60° C. for 24 h. The reactionwas diluted with a 1 to 4 mixture of water and an organic phase made ofdiethyl ether and ethyl acetate and then separated. The organic phaseswere dried with brine and solid sodium chloride. The liquor obtainedafter removal of the volatiles was purified over silica gel (ethylacetate/dichloromethane). The product solidified on standing.

General Procedure 1

To an aryl bromide (1.4-1.6 eq.), was added(2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pentanamide(1 eq.) in tetrahydrofuran/propanol 4/1 (0.05M) and 2M aqueous sodiumcarbonate (3 eq.). The solution was briefly degassed by bubblingnitrogen through the solution and a palladium acetate andtriphenylphosphine mixture in a 1:3 ratio (0.01-0.15 eq.) was added. Thereaction was heated to 80° C. for 24 h. The reaction was cooled down anddiluted with dichloromethane (acid acetic was added in the case of anacidic compound) and then filtered through a SPE tube of silica gel. Theconcentrated liquor was purified on a reverse phase (C₄) HPLC-MS column.

The following compounds were synthesized using general procedure 1. NAMECHARACTERIZATION (2S)-2-[[4-(3-chloropyrazin-2- MS (−ESI): 447.3 [M −1]⁻ yl)phenyl](phenyl)methoxy]-N- (cyanomethyl)-4-methylpentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 418.4 [M − 1]⁻{phenyl[4-(1,3-thiazol-2- yl)phenyl]methoxy}pentanamide(2S)-2-[[4′-(aminosulfonyl)-1,1′-biphenyl- MS (−ESI): 490.4 [M − 1]⁻4-yl](phenyl)methoxy]-N-(cyanomethyl)-4- methylpentanamide(2S)-N-(cyanomethyl)-4-methyl-2-[[4′- MS (−ESI): 489.4 [M − 1]⁻(methylsulfonyl)-1,1′-biphenyl-4- yl](phenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 462.4 [M − 1]⁻[phenyl(4-quinolin-3- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 413.4 [M − 1]⁻[phenyl(4-pyrimidin-5- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 462.4 [M − 1]⁻[phenyl(4-quinolin-8- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-2-[{4-[6- MS (−ESI): 458.4 [M − 1]⁻(hydroxymethyl)-1-oxidopyridin-3- yl]phenyl}(phenyl)methoxy]-4-methylpentanamide (2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 412.4 [M −1]⁻ [phenyl(4-pyridin-4- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-2-[[4-(1H-indol-4- MS (−ESI): 450.4 [M − 1]⁻yl)phenyl](phenyl)methoxy]-4- methylpentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 412.3 [M − 1]⁻[phenyl(4-pyridin-2- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 413.5 [M − 1]⁻[phenyl(4-pyrazin-2- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 412.5 [M − 1]⁻[phenyl(4-pyridin-3- ylphenyl)methoxy]pentanamide(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 480.5 [M − 1]⁻(phenyl{4-[5-(2H-tetraazol-5-yl)pyridin-3- yl]phenyl}methoxy)pentanamide(2S)-N-(cyanomethyl)-4-methyl-2-[[4-(3- MS (−ESI): 426.5 [M − 1]⁻methylpyridin-2- yl)phenyl](phenyl)methoxy]pentanamide 2-{4-[[((1S)-1-MS (−ESI): 456.5 [M − 1]⁻ {[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]phenyl} isonicotinic acid(2S)-N-(cyanomethyl)-4-methyl-2- MS (−ESI): 413.5 [M − 1]⁻[phenyl(4-pyrimidin-2- ylphenyl)methoxy]pentanamide ethyl 4′-[[((1S)-1-MS (−ESI): 483.4 [M − 1]⁻ {[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′- biphenyl-4-carboxylate4′-[[((1S)-1- MS (−ESI): 454.5 [M − 1]⁻{[(cyanomethyl)amino]carbonyl}-3- methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-carboxamide

EXAMPLE 17 Synthesis ofN-(cyanometbyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamideStep 1 methyl 4-[hydroxy(phenyl)methyl]benzoate

To a solution of methyl 4-formylbenzoate (2.83 g, 17.2 mmoles) at −78°C. in 60 mL of dichloromethane is added 10 mL a 2.0 M solution ofphenylmagnesium chloride in tetrahydrofuran (20.0 mmoles) over 7minutes. After stirring for an additional 20 minutes, the reaction wasquenched with methanol then with saturated aqueous ammonium chloride.The aqueous layer was acidified with 1N hydrochloric acid and the phaseswere separated. The oragnic portion was washed with saturated aqueoussodium bicarbonate, brine and dried over magnesium sulfate. Removal ofthe volatiles under reduced pressure and purification over silica gelafforded the title ester.

Step 2 4-[hydroxy(phenyl)methyl]benzoic acid

To a solution of methyl 4-[hydroxy(phenyl)methyl]benzoate from step 1(1.6 g, 6.6 mmol) in THF (40 mL) was added methanol (13 mL) and 1.0Naqueous potassium hydroxide solution (13.2 mL, 13.2 mmol). The mixturewas heated at 70° C. for 20 minutes and then cooled down to roomtemperature. Methanol and TBF were evaporated under reduced pressure.3.0N hydrochloric acid (7.5 mL, 22.5 mmol) was added to the cruderesidue. The solid obtained was filtered to afford the title acid as awhite solid. The resulting crude compound was used as such in the nextstep.

Step 3 tert-butyl4-{4-[hydroxy(phenyl)methyl]benzoyl}piperazine-1-carboxylate

To a solution of the crude compound of 4-[hydroxy(phenyl)methyl]benzoicacid (1.51 g, 6.6 mmnol) in DMF (33 mL) was added tert-butylpiperazine-1-carboxylate (1.23 g, 6.6 mmol), triethylamine (3.7 mL, 26.5mmol) and HATU (2.51 g, 6.6 mmol). The mixture was aged for 3 hoursunder a nitrogen atmosphere and was then poured into a saturated aqueoussolution of NaHCO₃. The resulting mixture was extracted 3 times withethyl acetate. The combined organic layers were washed with brine, driedand evaporated to a solid which was stirred in ethyl acetate at roomtemperature for 2 hours. The title compound was then recovered byfiltration as a white solid.

Step 4 tert-butyl4-{4-[[1-(methoxycarbonyl)-3-methylbutoxy](phenyl)methyl]benzoyl}piperazine-1-carboxylate

To a solution of tert-butyl4-{4-[hydroxy(phenyl)methyl]benzoyl}piperazine-1-carboxylate from step 3(1.5 g, 3.8 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (0.16g, 4.0 mmol) portionwise. The mixture was aged 15 minutes under anitrogen atmosphere and methyl 2-bromo-4-methylpentanoate (0.65 mL, 4.0mmol) was added dropwise. The reaction was allowed to warm to roomtemperature and was aged for 3 hours. The mixture was then partitionedbetween ethyl acetate and brine and the organic layer was dried andevaporated. The crude product was chromatographed on silica gel using40% ethyl acetate in hexanes to afford the title compound.

Step 52-[(4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}phenl)(phenyl)methoxyl-4-methylpentanoicacid potassium salt

To a solution of tert-butyl4-{4-[[1-(methoxycarbonyl)-3-methylbutoxy](phenyl)methyl]benzoyl}piperazine-1-carboxylatefrom step 3 (0.6 g, 1.1 mmol) in THEF (6.5 mL) was added methanol (2.2mL) and 1.0N aqueous potassium hydroxide solution (2.2 mL, 2.2 mmol).The mixture was heated at 70° C. for 20 minutes and then cooled down toroom temperature. The crude mixture was evaporated under reducedpressure and co-evaporated twice with toluene. The solid residueobtained was used as such in the next step.

Step 6 tert-butyl4-{4-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)(phenyl)methyl]benzoyl}piperazine-1-carboxylate

Using the same procedure as described in step 3,2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanoicacid potassium salt from step 4 (0.55 g, 1.1 mmol) was coupled withamino acetonitrile HCl salt. The crude product was chromatographed onsilica gel using 5% methanol in dichloromethane to afford the titlecompound as a white solid.

Step 7N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide

Tert-butyl4-{4-[(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)(phenyl)methyl]benzoyl}piperazine-1-carboxylatefrom step 6 (0.09 g, 0.16 mmol) was dissolved in formic acid (1 mL). Themixture was aged for 2 hours and evaporated under reduced pressure. Thecrude residue was neutralized using a saturated aqueous solution ofNaHCO₃. The mixture was extracted 3 times with dichloromethane and theorganic layers were dried and evaporated. The crude product waschromatographed on silica gel using 1% NH₄OH and 9% methanol indichloromethane to afford the title compound as a white solid.

MS (+APCI) 449.1 [M+1]⁺

EXAMPLE 18 Synthesis ofN-(cyanomethyl)-2-[(4-{[4-(2-fluoroethyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanamide

To a solution ofN-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamidefrom example 17, step 7 (79 mg, 0.18 mmol) in acetonitrile (1 mL), wasadded Na₂CO₃ (37 mg, 0.36 mmol) and 2-bromofluoroethane (39 μL, 0.525mmol). The reaction was heated in a sealed tube at 85° C. for 16 hoursand was then cooled down to room temperature. The mixture was thenconcentrated and the crude residue chromatographed on silica gel using1% NH₄OH and 9% methanol in dichloromethane to afford the titlecompound.

MS (−ESI) 493.1 [M−1]⁻

EXAMPLE 19 Preparation of L-000873736-000G001 Synthesis ofN-(cyanomethyl)-4-methyl-2-[(4-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}phenyl)(phenvl)methoxy]pentanamide

To a solution ofN-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamidefrom example 17, step 7 (102 mg, 0.23 mmol) in DMF (1 mL), was addedmethyl sulfonyl chloride (27 μL, 0.35 mmol) and cesium carbonate (91 mg,0.28 mmol). The mixture was aged for 2 hours under nitrogen atmosphereand was diluted with dichloromethane. The resulting mixture was filteredover celite and concentrated under reduced pressure. The crude residuewas chromatographed on silica gel using 1% NH₄OH and 9% methanol indichloromethane to afford the title compound.

MS (−APCI) 525.3 [M−1]⁻

EXAMPLE 20 Synthesis of(2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1 (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one

The title compound was prepared following Step 1 of Example 1.

Step 2(2S)-2-}[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-4-methylpentanoicacid

To a solution of 2-bromothiophene (326 mg, 2.0 mmol) in ether (8 mL) wasadded magnesium turnings (51 mg, 2.1 mmol). The mixture was heated at50° C. for 1 hour, under a nitrogen atmosphere. The grignard solutionwas then cooled down to −40° C. and aged until addition. In a secondflask, cooled at −40° C., a 0.2M solution of(5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one in ether, from step1 (5.0 mL, 1.0 mmol) was added dropwise to a 1.0M solution of zincchloride in ether (5.0 mL, 5 mmol). Finally, the grignard solution wasadded dropwise to the zinc chloride mixture and the reaction was agedfor 30 minutes at −40° C. The mixture was allowed to warm to 0° C. andaged for 4 hours. The reaction was then poured into a saturated aqueoussolution of NH₄Cl and the resulting mixture was extracted 3 times withEt₂O. The organic layers were washed with brine, dried and evaporated.The crude product was chromatographed on silica gel using 30% ethylacetate in hexanes to afford the title compound.

Step 3(2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

To a solution of(2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-4-methylpentanoicacid from step 2, (273 mg, 0.71 mmol) in DMF (3.5 mL) was addedaminoacetonitrile HCL salt (66 mg, 0.71 mmol), triethylamine (359 μL,3.55 mnmol) and HATU (270 mg, 0.71 mmol). The mixture was aged for 3hours under a nitrogen atmosphere and was then poured into a saturatedaqueous solution of NaHCO₃. The resulting mixture was extracted 3 timeswith ethyl acetate. The organic extracts were washed with brine, driedand evaporated to a solid. The crude product was chromatographed onsilica gel using 35% ethyl acetate in hexanes to afford the titlecompound.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): (8.7-8.6, m, 1H); (7.6, d, 3H); (7.4,d, 2H); (7.1, s, 1H); (7.0, t, 1H); (5.7, s, 1H); (4.1, d, 2H);(3.9-3.8, m, 1H); (1.8-1.7, m, 1H); (1.7-1.6, m, 1H); (1.4-1.3, m, 1H);(0.9, d, 3H); (0.7, d, 3H).

EXAMPLE 21 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(thien-2-yl)methyl]oxy}pentanamide

To a solution of(2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide,from example 20, step 3 (113 mg, 0.27 mmol) in DMF (3 mL) was added4-piperazin-1-ylphenylboronic acid (73 mg, 0.30 mmol), and a 2.0Maqueous solution of Na₂CO₃ (0.54 mL, 1.08 mmol). The mixture was placedunder vacuum and purged with nitrogen 3 times before the PdCl₂(dppf)₂was added (10 mg, 0.014 mmol). The reaction mixture was purged 3 othertimes with nitrogen and the reaction was heated to 85° C. for 16 hours.The mixture was then diluted with dichloromethane and filtered overcelite. The organic layer was isolated and washed with a saturatedsolution of NaHCO₃ and brine, dried and evaporated. The crude residuewas chromatographed on silica gel using 1% NH₄OH and 9% methanol indichloromethane to afford the title compound.

MS (+APCI) 503.1 [M+1]⁺

EXAMPLE 22 Synthesis of(2S)-2-[(4-bromophenyl)(thien-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-bromophenyl)(thien-3-yl)methanol

To a solution of 1.5M BuLi in hexanes (3.5 mL, 5.25 mmol) in THF (6.5mL) cooled to −78° C. was added 3-bromothiophene dropwise (469 μL, 5.0mmol). The mixture was stirred for 30 minutes and a 1.0M solution of4-bromobenzaldehyde in TBF was slowly added (5.5 mL, 5.5 mmol). Thereaction was warmed to 0° C. and aged for 1 hour. The mixture was thenpoured into a saturated aqueous solution of NH₄Cl. The resulting mixturewas extracted 3 times with ethyl acetate and the organic layers werewashed with brine, dried and evaporated. The crude residue waschromatographed on silica gel using a gradient of 10-25% ethyl acetatein hexanes to afford the title compound.

Step 2 (4-bromophenyl)(thien-3-yl)methyl 2,2,2-trichloroethammidoate

To a solution of (4-bromophenyl)(thien-3-yl)methanol from step 1 (632mg, 2.36 mmol) in diethyl ether (2.5 mL) at 0° C. was added sodiumhydride (6 mg, 0.24 mmol). Then trichloroacetonitrile was added dropwise(237 μL, 2.36 mmol) over 15 minutes and the reaction was allowed to warmto room temperature for 3 hours. The reaction was then filtered overcelite and concentrated under reduced pressure. The resulting crudecompound was used as such in the next step.

Step 3(2S)-2-[(4-bromophenyl)(thien-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

To a solution of (4-bromophenyl)(thien-3-yl)methyl2,2,2-trichloroethanimidoate from step 2 (970 mg, 2.36 mmol) indichloromethane (12 mL) was added(2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (402 mg, 2.36 mmol)and camphorsulfonic acid (137 mg, 0.59 mmol). The reaction was stirredovernight at room temperature and the resulting mixture was poured intowater. The aqueous layer was extracted 3 times with ethyl acetate. Thecombined organic layers were washed with brine, dried and evaporated andthe crude residue was chromatographed on silica gel using 50% ethylacetate in hexanes to afford the title compound.

MS (−APCI) 419.0 [M−1]⁻

EXAMPLE 23 Synthesis of2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-bromophenyl)(pyridin-2-yl)methanol

Using the same protocol as described in example 22, step 1,2-bromopyridine (477 μL, 5.0 mmol) was added to 4-bromobenzaldehyde(1.018 g, 5.5 mmol). The crude residue obtained was chromatographed onsilica gel using 50% ethyl acetate in hexanes to afford the titlecompound.

Step 2 methyl2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoate

To a solution of (4-bromophenyl)(pyridin-2-yl)methanol from step 1 (720mg, 2.73 mmol) in DMF (14 mL) at 0° C., was added sodium hydrideportionwise (69 mg, 2.87 mmol). The mixture was stirred 30 minutesbefore the methyl 2-bromo-4-methylpentanoate was slowly added (469 μL,2.87 mmol). The reaction was allowed to warm to room temperature and wasaged for 3 hours more. The mixture was then poured into brine andextracted 3 times with ethyl acetate. The combined organic extracts weredried and concentrated and the crude product obtained waschromatographed on silica gel using 50% ethyl acetate in hexanes toafford the title compound.

Step 3 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoic acidpotassium salt

Using the same protocol as described in example 17, step 5, methyl2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoate from step 2(623 mg, 1.59 mmol) was hydrolysed with potassium hydroxide. The solidresidue obtained was used as such in the next step.

Step 42-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same protocol as described in example 17, step 3,2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-4-methylpentanoic acidpotassium salt from step 3 (662 mg, 1.59 mmol) was coupled withaminoacetonitrile HCl Salt. The crude residue obtained waschromatographed on silica gel using 50% ethyl acetate in hexanes toafford the title compound.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm) mixture of 4 diastereoisomers: (9.6,bs, 1 H); (8.7, d, 1H); (8.5, d, 1H); (8.1, bs, 1H); (7.9-7.8, m, 2 H);(7.7-7.6, m, 3H); (7.5-7.4, m, 6H); (7.4-7.3, m, 2H); (7.2, d, 1H);(5.65, s, 1H); (5.6, s, 1H); (4.3, d, 2H); (4.2, d, 2H); (4.0-3.9, m,2H); (2.9-2.8, m, 1H); (2.8-2.6, m, 3H); (1.6-1.5, m, 2H); (1.95, d,3H); (1.9, d, 3H); (1.75, 3H); (1.65, 3H).

EXAMPLE 24 Synthesis of2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-bromophenyl)(pyridin-3-yl)methanol

Using the same protocol as described in example 22, step 1,3-bromopyridine (482 μL, 5.0 mmol) was added to 4-bromobenzaldehyde(1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gelusing 1% NH₄OH and 9% MeOH in dichloromethane to afford the titlecompound.

Step 2 methyl2-[(4-bromophenyl)(pyridin-3-yl)methoxyl-4-methylpentanoate

Using the same protocol as described in example 23, step 2,(4-bromophenyl)(pyridin-3-yl)methanol from step 1 (644 mg, 2.4 mmol) wasadded to methyl 2-bromo-4-methylpentanoate (412 μL, 2.52 mmol). Thecrude residue was chromatographed on silica gel using 50% ethyl acetatein hexanes to afford the title compound.

Step 3 2-[(4-bromophenpl)(pyridin-3-yl)methoxy]-4-methylpentanoic acidpotassium salt

Using the same protocol as described in example 17, step 5, methyl2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-4-methylpentanoate from step 2(268 mg, 0.68 mmol) was hydrolysed with potassium hydroxide. The solidresidue obtained was used as such in the next step.

Step 42-[(4-bromophenyl)(pyridin-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same protocol as described in example 17, step 3,2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-4-methylpentanoic acidpotassium salt from step 3 (132 mg, 0.35 mmol) was coupled withaminoacetonitrile HCl Salt. The crude residue obtained waschromatographed on silica gel using 10% MeOH in dichloromethane toafford the title compound.

MS (−ESI) 414.2 [M−1]⁻

EXAMPLE 25 Synthesis of2-[(4-biomohenyl)(pyridin-4-yl)methoxy]-N-(cyanomethyl)-4-methylgentanamideStep 1 4-bromophenyl)(pyridin-4-yl)methanol

Using the same protocol as described in example 22, step 1,4-bromopyridine (790 mg, 5.0 mmol) was added to 4-bromobenzaldehyde(1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gelusing 1% NH₄OH and 9% MeOH in dichloromethane to afford the titlecompound.

Step 2 methyl2-[(4-bromophenyl)(pyridin-4-yl)methoxyl-4-methylpentanoate

Using the same protocol as described in example 23, step 2,(4-bromophenyl)(pyridin-4-yl)methanol from step 1 (594 mg, 2.20 mmol)was added to methyl 2-bromo-4-methylpentanoate (377 μL, 2.31 mmol). Thecrude residue was chromatographed on silica gel using 50% ethyl acetatein hexanes to afford the title compound.

Step 3 2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoic acidpotassium salt

Using the same protocol as described in example 17, step 5, methyl2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoate from step 2(293 mg, 0.75 mmol) was hydrolysed with potassium hydroxide. The solidresidue obtained was used as such in the next step.

Step 42-[(4-bromophenyl)(pyridin-4-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same protocol as described in example 17, step 3,2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-4-methylpentanoic acidpotassium salt from step 3 (312 mg, 0.75 mmol) was coupled withaminoacetonitrile HCl Salt. The crude residue obtained waschromatographed on silica gel using 10% MeOH in dichloromethane toafford the title compound.

MS (+ESI) 416.2 [M+1]⁺

EXAMPLE 26 Synthesis ofN-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(pyridin-2-yl)methoxy]pentanamide

Using the same protocol as described in example 21,2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamidefrom example 7, step 4 (241 mg, 0.58 mmol) was coupled with4-piperazin-1-ylphenylboronic acid (155 mg, 0.64 mmol). The cruderesidue obtained was chromatographed on silica gel using 1% NH₄OH and 9%MeOH in dichloromethane to afford the title compound.

MS (+APCI) 498.3 [M+1]⁺

EXAMPLE 27 Synthesis of2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-bromophenyl)(1,3-thiazol-2-yl)methanol

Using the same protocol as described in example 22, step 1,2-bromothiazole (451 μL, 5.0 mmol) was added to 4-bromobenzaldehyde(1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gelusing 50% ethyl acetate in hexanes to afford the title compound.

Step 2 methyl2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoate

Using the same protocol as described in example 23, step 2,(4-bromophenyl)(1,3-thiazol-2-yl)methanol from step 1 (983 mg, 3.64mmol) was added to methyl 2-bromo-4-methylpentanoate (624 μL, 3.82mmol). The crude residue was chromatographed on silica gel using 25%ethyl acetate in hexanes to afford the title compound.

Step 3 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoicacid potassium salt

Using the same protocol as described in example 17, step 5, methyl2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoate fromstep 2 (441 mg, 1.11 mmol) was hydrolysed with potassium hydroxide. Thesolid residue obtained was used as such in the next step.

Step 42-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same protocol as described in example 17, step 3,2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoic acidpotassium salt from step 3 (427 mg, 1.11 mmol) was coupled withaminoacetonitrile HCl Salt. The crude residue obtained waschromatographed on silica gel using 50% ethyl acetate in hexanes toafford the title compound.

MS (−APCI) 420.8 [M−1]⁻

EXAMPLE 28 Synthesis ofN-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(1,3-thiazol-2-yl)methoxy]pentanamide

Using the same protocol as described in example 21,2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamidefrom example 27, step 4 (225 mg, 0.53 mmol) was coupled with4-piperazin-1-ylphenylboronic acid (141 mg, 0.58 mmol). The cruderesidue obtained was chromatographed on silica gel using 1% NH₄OH and 9%MeOH in dichloromethane to afford the title compound.

MS (+APCI) 504.2 [M+1]⁺

EXAMPLE 29 Synthesis of(2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-bromophenyl)(4-fluorophenyl)methanol

To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at−78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). Themixture was stirred at −78° C. for 0.5 h., 4-fluorobenzaldehyde (42.4mmol, 5.3 g) was added. The mixture was stirred at −78° C. for 1 h andthen warmed to r.t. The reaction mixture was diluted with EtOAc, washedwith NaHCO₃ and brine. The organic extract was dried (anhyd. MgSO4) andconcentrated under reduced pressure to give an oil. Chromatography gavethe title compound.

Step 2 (4-Bromophenyl)(4-fluorophenyl)methyl2,2,2-trichloroethanimidoate

Sodium Hydride (60%, 0.356 mmol) was suspended in Et₂O (2 mL) and asolution of (4-bromophenyl)(4-fluorophenyl)methanol (3.56 mmol, 281 mg)in 2 mL Et₂O was added. The mixture was stirred at r.t. for 0.25 h. Themixture was cooled to 0° C., Trichloroacetonitrile (3.38 mmol, 144 mg)was added. The mixture was allowed to warmed to r.t. over 1 h. Thereaction mixture was concentrated to an oil and pentane containing 0.36mmol of MeOH was added with vigorous stirring. The mixture was filteredand washed with pentane. Concentration of the filtrate gave the crudeimidate which was used as such without further purification.

Step 3 Methyl(2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoate

To a solution of the (4-bromophenyl)(4-fluorophenyl)methyl2,2,2-trichloroethanimidoate of step 2 (1.18 mmol, 500 mg) in CH₂Cl₂ (5mL) was added L-leucic acid methyl ester 2 (1.18 mmol, 146 mg) and thencamphor sulfonic acid (0.12 mmol, 27 mg). The mixture was stirred atr.t. for 18 h. A few drops of saturated NaHCO3 was added, The mixturewas diluted with ether and filtered. The filtrate was concentrated underreduced pressure and the crude product was chromatographed to give thetitle compound.

Step 4 (2S)-2-[(4-Bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoicacid

To a suspension of methyl(2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoate ofstep 3 (0.38 mmol, 157 mg) in MeOH/THF/H₂O (1:2:2 mL) was added LiOHmonohydrate (0.96 mmol, 40 mg). The mixture was stirred at r.t. for 2 h.HCl (1N) was added until pH 1. The mixture was extracted with CH₂Cl₂.The combined extracts were dried over anhydrous, MgSO4 and concentrated.The crude acid was used without further purification.

Step 5(2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

To a solution of(2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-4-methylpentanoic acidof step 4 (0.35 mmol, 151 mg) in DMF (3 mL) was added aminoacetonitrilehydrochloride (0.38 mmol) and HATU (0.38 mmol, 145 mg).Diisopropylethylamine (0.96 mmol, 123 mg) was added last, the mixturewas stirred at r.t. for 3 days. Ether was added, followed by 1 N HCl.The mixture was separated after agitation. The organic extract waswashed with 0.1 N HCl, water and brine and dried over anhyd. MgSO4.Concentration of the organic extracts followed by chromatography gavethe title amide.

MS (−ESI): 433.2 [M−1]⁻

EXAMPLE 30 Synthesis of(2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (4-Bromophenyl)(cyclohexyl)methanol

To a solution of 1,4-dibromobenzene (42.4 mmol, 10 g) in THF (100 mL) at−78° C. was added dropwise n-BuLi (42.4 mmol, 2 M in hexane). Themixture was stirred at −78° C. for 0.5 h., cyclohexanecarboxaldehyde(42.4 mmol, 4.8 g) was added. The mixture was stirred at −78° C. for 0.5h and then warmed to r.t. The reaction mixture was diluted with EtOAc,washed with NaHCO₃ and brine. The organic extract was dried (anhyd.MgSO₄) and concentrated under reduced pressure to give an oil.Chromatography gave the title compound.

Step 2 (4-Bromophenyl)(cyclohexyl)methyl 2,2,2-trichloroethanimidoate

Sodium Hydride (60%, 0.74 mmol) was suspended in Et₂O (8 mL) and asolution of (4-bromophenyl)(cyclohexyl)methanol of step 1 (7.4 mmol, 2.0g) in 8 mlL Et₂O was added. The mixture was stirred at r.t. for 0.25 h.The mixture was cooled to 0° C., Trichloroacetonitrile (7.4 mmol, 1.07g) was added. The mixture was allowed to warmed to r.t. over 1 h. Thereaction mixture was diluted with EtOAc, washed with NaHCO₃ and driedover anhyd. MgSO4. Concentration of the organic extract gave the crudeimidate as a yellow solid which was used without further purification.

Step 3(2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

To a solution of (4-bromophenyl)(cyclohexyl)methyl2,2,2-trichloroethanimidoate of step 2 (4.18 mmol, 1.73 g) in CH₂Cl₂ (15mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide fromStep 1, Example 67 (4.18 mmol, 0.71 g) and then PPTS (0.42 mmol, 0.105g). The mixture was stirred at r.t. for 72 h. A red solution resulted.The mixture was diluted with EtOAc and washed with NaHCO₃. The organicextract was dried (anhyd. MgSO4) and concentrated under reduced pressureto give an oil. Chromatography gave the less polar diastereomer and themore polar isomer.

MS (−ESI) 419.1 [M−1]⁻ for each isomer.

EXAMPLE 31 Synthesis of(25)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamideStep 1 1-(4-bromophenyl)-2-methylprop-2-en-1-ol

To a cold (−78° C.) solution of 1,4-dibromobenzene 1 (42.4 mnmol, 10 g)in TBF (60 mL) was added butyl lithium(42.4 mmol, 2.5 M in hexane). Themixture was stirred at −78° C. for 1 h. 2-methylpropenal (42.4 mmol,2.97 g) was added. The mixture was stirred at −78° C. for 1 h. NH4Cl wasadded. The mixture was extracted with EtOAc. The organic extract waswashed with brine, dried and concentrated to an oil. Chromatography(5-15% EtOAc/hexane) gave the desired alcohol.

Step 2 1-(4-Bromophenyl)-2-methylprop-2-enyl2,2,2-trichloroethanimidoate

Sodium Hydride (60%, 1.1 mmol) was suspended in Et₂O (14 mL) and asolution of alcohol 1 (11 mmol, 2.5 g) in Et₂O (7 mL) was added. Themixture was stirred at r.t. for 0.25 h. The mixture was cooled to 0° C.,Trichloroacetonitrile (11 mmol, 1.59 g) was added. The mixture wasallowed to warmed to r.t. over 1 h. The reaction mixture was dilutedwith EtOAc, washed with NaHCO3 and dried over anhyd. MgSO4.Concentration of the extract gave the crude imidate which waschromatographed to give the title compound.

Step 3(2S)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

To a solution of 1-(4-bromophenyl)-2-methylprop-2-enyl2,2,2-trichloroethanimidoate of step 2 (0.81 mmol, 300 mg) in CH₂Cl₂ (6mL) was added (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide fromStep 1, Example 67 (0.81 mmol, 137 mg) and then PPTS (0.081 mmol, 20mg). The mixture was stirred at r.t. for 72 h. The mixture was dilutedwith EtOAc and washed with NaHCO3. The organic extract was dried (anhyd.MgSO4) and concentrated under reduced pressure to give an oil.Chromatography (10% Acetone/EtOAc) gave 2 diastereomers (20 mg each).

MS (−ESI) 377.2 [M−1]⁻ for each diastereomer.

EXAMPLE 32 Synthesis of(2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 1-(4-Bromophenyl)-2-methylpropan-1-ol

To a solution of 4-brombenzaldehyde (27 mmol, 5.0 g) in THF (20 mL) wasadded at −78° C. a solution of isopropylmagnesium chloride (41 mmol,20.2 mL, 2M in ether). The mixture was stirred at −78° C. for 1 h andwarmed to 0° C. for 1 h. NH4Cl was added an the mixture was extractedwith EtOAc. The organic extract was washed with brine, dried andconcentrated to an oil. Chromatography (5-15% EtOAc/hexane) gave thedesired alcohol.

Step 2 1-(4-Bromophenyl)-2-methylpropyl 2,2,2-trichloroethanimidoate

Sodium Hydride (60%, 0.87 mmol) was suspended in Et2O (9 mL) and asolution of 1-(4-bromophenyl)-2-methylpropan-1-ol of step 1 (8.7 mmol,2.0 g) in Et2O (6 mL) was added. The mixture was stirred at r.t. for0.25 h. The mixture was cooled to 0° C. Trichloroacetonitrile (11 mmol)was added. The mixture was allowed to warmed to r.t. over 1 h. Themixture was diluted with EtOAc and washed with NaHCO3. The organicextract was dried (anhyd. MgSO4) and concentrated under reduced pressureto give an oil. Chromatography (10% Acetone/EtOAc) gave the titlecompound.

Step 3(2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamide

To a solution of the 1-(4-bromophenyl)-2-methylpropyl2,2,2-trichloroethanimidoate (2.6 mmol, 0.97 g) in CH₂Cl₂ (15 mL) wasadded (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from Step 1,Example 67 (3.9 mmol, 0.66 g) and then PPTS (0.26 mmol, 65 mg). Themixture was stirred at r.t. for 20 h. The mixture was diluted with EtOAcand washed with NaHCO3. The organic extract was dried (anhyd. MgSO4) andconcentrated under reduced pressure to give an oil. Chromatography (10%Acetone/EtOAc) gave 2 diastereomers.

MS (−ESI) 379.1 [M−1]⁻ for each diastereomer.

EXAMPLE 33 Synthesis of(2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylthio)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide

To a solution of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide(0.84 mmol, 348 mg) in toluene (5 mL) and n-propanol (1.5 mL) was addedunder a stream of nitrogen 4-(methylthio)phenylboronic acid (1.0 mmol,169 mg), Pd(PPh₃)₄ (0.042 mmol, 48 mg), Na₂CO₃ (2 M, 2 mL). The mixturewas degassed with a rapid stream of nitrogen bubbling through themixture and the mixture was heated to 100° C. for 2 h. The mixture wascooled, diluted with EtOAc and washed with water. The product wasisolated by chromatography (40% EtOac/Hexane).

MS (−ESI) 457 [M−1]⁻

EXAMPLE 34 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl](phenol)methyl]oxy}pentanamide

To a solution of(2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylthio)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamidefrom Example 33 (0.60 mmol, 274 mg) in CH₂Cl₂ was added m-CPBA (1.5rnmol, 268 mg, 80%) at 0° C. The mixture was stirred at 0° C. for 1 h.The mixture was warmed to r.t. and stirred for 3 h. The mixture wasdiluted with EtOAc and washed with Na₂CO₃, NaHCO₃, brine and dried(anhyd. MgSO₄). The organic extract was concentrated under reducedpressure and the residue was chromatographed to give the title compound.

MS (−ESI) 489 [M−1]⁻

EXAMPLE 35 Synthesis of(2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-(4′-morpholin-4-yl-1,1′-biphenyl-4-yl)(phenyl)methyl]oxy}pentanamideStep 1 4-(4-Bromophenyl)morpholine

To a solution of of morpholine (0.85 mmol, 739 mg) in dioxane (12 mL)was added 1,4-dibromobenzene (21.2 mmol, 5 g),2-(di-t-butylphosphine)biphenyl (1.02 mmol, 304 mg), potassiumt-butoxide (25.5 mmol, 2.47 g) and Pd₂(dba)₃ (0.254 mmol, 233 mg) Themixture was degassed under a stream of nitrogen and then heated toreflux for 20 h. The mixture was diluted with EtOAc and washed withwater and brine. The organic extract was concentrated under reducedpressure and the residue was chromatographed to give the desiredproduct.

Step 2(2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-(4′-morpholin-4-yl-1,1′-biphenyl-4-yl)(phenyl)methyl]oxy}pentanamide

To a solution of N-(4-bromophenyl)morpholine (0.66 mmol, 159 mg) in DMF(7 mL) was added under a stream of nitrogen(2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxy}pentanamidefrom Example 16 (0.66 mmol, 250 mg). PdCl₂(dppf) (0.033 mmol, 24 mg) and2N Na₂CO₃ (2.63 mmol) was added. The mixture was degassed with a rapidstream of nitrogen bubbling through the mixture and the mixture washeated to 85° C. for 18 h. EtOAc was added, the mixture was washed withwater and brine. The organic extract was dried and chromatographed(20-40% EtOAc/hexane) to give the title compound.

MS (−ESI) 496 [M−1]⁻

EXAMPLE 36 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(5-methylcyclohex-1-en-1-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 1methyl(2S)-2-}[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoate

To a solution of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acidfrom step 2 example 1, (2.5 g, 6.6 mmol) in methanol (25 mL) at 0° C.was added portionwise diazomethane in diethyl ether until the yellowcolor persisted. A few drops of acetic acid were then added to quenchthe excess diazomethane. The colorless solution was concentrated andthen the volatiles were coevaporated twice with n-heptane. The oil waspumped on to remove the last traces of solvent.

¹H NMR (500 MHz, DMSO-d₆) δ 7.53 (d, 2H), 7.40-7.26 (m, 7H), 5.48 (s,1H), 3.89-3.82 (m, 1H), 3.65 (s, 3H), 1.80-1.63 (m, 2H), 1.45-1.35 (m,1H), 0.85 (d, 3H), 0.53 (d, 3H).

Step 2 methyl(2S)-4methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy)}pentanoate

To a mixture of methyl(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoate fromexample 68 (1.88 g, 4.8 mmol) and pyridine-3-boronicacid-1,3-propanediol cyclic ester (862 mg, 5.29 mmol) in DMF (48 mL) wasadded 2 molar sodium carbonate (9.6 mL). The mixture was degased 3 timesusing nitrogen. Added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1) (175 mg, 0.24 mmol). Degassed 3 more timeswith nitrogen. The mixture was inserted in an oil bath at 85° C. andstirred for 2.5 hr. The mixture was added to water (250 mL) andextracted with ethyl acetate (200 mL). Separated the layers and washedthe organics with dilute brine (50 mL). Dried (Na₂SO₄), filtered,concentrated and chromatographed the residue on silica gel using 40%ethyl acetate in toluene as eluent to obtain the title compound as anoil.

MS (+APCI) 390.0 [M+1]⁺

Step 33-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide

A solution of methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanoatefrom example 36 step 2 (881 mg, 2.26 mmol) and iodomethane (3.2 g, 22.6mmol) in acetonitrile (22 mL) was heated in a pressure tube immersed inan oil bath at 120° C. for 18 hours. The solution was concentrated andthe residue pumped on to obtain the pyridinium iodide salt as a foam.

¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.95 (d, 2H), 8.86 (d, 1),8.20 (t, 1H), 7.84 (d, 2H), 7.59 (d, 2H), 7.48-7.30 (m, 5H), 5.63 (s,1H), 4.42 (s, 3H), 3.98-3.88 (m, 1H), 3.66 (s, 3H), 1.89-1.67 (m, 2H),1.54-1.35 (m, 1H), 0.90 (d, 3H), 0.68 (d, 3H).

Step 4 methyl(2S)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate

To a solution of3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide from example 36 step 3 (1.45 g, 2.72 mmol) in methanol (25 mL)was added in portions sodium cyanoborohydride (4.25 g, 67.6 mmol). Themixture was heated at 65° C. for 1 h and then concentrated. The residuewas partitioned between diethyl ether (75 mL) and water (25 mL). Theseparated aqueous layer was extracted again with diethyl ether (75 mL).The combined ether layers were dried (Na₂SO₄), filtered, concentratedand chromatographed on silica gel using 10% methanol in dichloromethaneas eluent to obtain the title compound as an oil.

MS (+APCI) 408.2 [M+1]⁺

Step 5(2S)-N-(cyanomethyl)-4-methyl-2-}[(R)-[4-(5-methylcyclohex-1-en-1-yl)phenyl](phenyl)methyl]oxy}pentanamide

A solution of methyl(2S)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanoatefrom example 36 step 4 (100 mg, 0.25 mmol), TBF (1.5 mL), methanol (0.5mL) and IN KOH (0.5 mL) was heated at 70° C. for 45 min. The mixture wasconcentrated and then 2 times with toluene to dry. To the residue wasadded DMF (1.5 mL), aminoacetonitrile hydrochloride (23 mg, 0.25 mmol),HATU coupling reagent (95 mg, 0.25 mmol) and triethylamine (75 mg, 0.75mmol). The reagents were stirred at r.t. for 2 h, then added to dilutebrine (5 mL) and extracted with 1:1 TBF/ethyl acetate (25 mL). Theorganic layer was washed with brine (2×10 mL), dried (Na₂SO4), filtered,concentrated and the residue purified by chromatography on silica gelusing 10% methanol in dichloromethane to obtain the title compound as awhite solid.

MS (+APCI) 432.2 [M+1]⁺

EXAMPLE 37 Synthesis of3-{4-[(R)-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy}(phenyl)methyl]pheny}-1-methylpyridiniumiodide

Using the same procedure as described for example 36 step 3(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide(150 mg, 0.36 mmol) was converted to its pyridinium iodide salt. Thesalt was swished with diethyl ether (20 mL) for 18 h and the titlecompound was filtered off as an amorphous solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.95 (d, 1H), 8.85 (d, 1H),8.69 (t, 1H), 8.19 (t, 1H), 7.84 (d, 2H), 7.63 (d, 2H), 7.47-7.29 (m,5H), 5.55 (s, 1H), 4.40 (s, 3H), 4.14 (d, 2H), 3.87-3.79 (m, 1H),1.84-1.63 (m, 2H), 1.47-1.38 (m, 1H), 0.87 (d, 3H), 0.73 (d, 3H).

EXAMPLE 38 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide

Using the same hydrolysis and coupling procedures as described in Step 5of example 36, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanoate(250 mg, 0.64 mmol was hydrolyzed and coupled to give the title compoundas a white solid.

MS (+APCI) 414.1 [M+1]⁺

EXAMPLE 39 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 1methyl(2S)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate

To avoid catalytic poisoning during the hydrogenation, the quaternarypyridinium salt was first washed to remove free iodide.3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide from step 3 in example 36 (3.58 g, 6.6 mmol) was dissolved indichloromethane (100 mL) and shaken with 5% sodium metabisulfite (30 mL)until the heavy red color dissipated. The organic layer was separated,dried (Na₂SO₄), filtered and concentrated to recover 3.2 g. of startingmaterial. A mixture of the quaternary salt (3.2 g, 6.0 mmol), methanol(150 mL), acetic acid (800 mg, 12 mmol) and platinum oxide (hydrated)79-84% (250 mg) was hydrogenated at 60 psi for 48 hours. The mixture wasfiltered, concentrated and then concentrated 2 times with n-heptane. Theresidue was chromatographed on silica gel using 5% methanol indichloromethane to obtain the title compound as a foam.

MS (+APCI) 410.2 [M+1]⁺

Step 1 Alternate Procedure

A mixture of methyl(2S)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanoatefrom step 4 in example 36 (300 mg, 0.73 mmol) ethanol (10 mL) aceticacid (87 mg, 1.46 mmol) and 10% palladium on charcoal (18 mg) washydrogenated for 48 h at 60 psi. The mixture was filtered, concentratedand then concentrated 2 times with n-heptane. The residue was pumped onto obtain the title compound as an oil.

MS (+APCI) 410.2 [M+1]⁺

Step 2(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy)pentanamide

Using the same hydrolysis and coupling procedures as described in step 5in example 36 (337 mg, 0.82 mmol) of methyl(2S)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy}pentanoatewas hydrolyzed and coupled to give the title compound as a white solid.

MS (+APCI) 434.2 [M+1]⁺

EXAMPLE 40 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide

To a solution of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamidefrom example 38 (95 mg, 0.23 mmol) in dichloromethane (10 mL) was added77% quality 3-chloroperoxybenzoic acid (51.5 mg, 0.23 mmol) at 5° C. Thetemperature was permitted to gradually rise to r.t. over 1.5 h. Themixture was concentrated and the residue partitioned between ethylacetate and 1M Na₂CO₃. The ethyl acetate layer was dried (Na₂SO₄) andconcentrated to yield 100 mg of the title compound. Purification bychromatography on silica gel using 10% methanol in dichloromethane andconcentating with diethyl ether 2 times gave a white solid.

MS (+APCI) 430.1 [M+1]⁺

EXAMPLE 41 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamideStep 13-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridinium bromide

A solution of methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanoatefrom example 36 step 2 (740 mg, 1.9 mmol) and 2-bromoethyl methyl ether(1.32 g, 9.5 mmol) in acetonitrile (10 mL) was heated in a pressure tubeemersed in an oil bath at 120+ C. for 18 hours. The mixture wasconcentrated and the residue slurried with diethyl ether (25 mL) 2 timesfollowed by decanting and then pumped on by high vacuum to obtain thetitle compound as a foam.

¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 9.0 (d, 1H), 8.93 (d, 1H),8.24 (t, 1H), 7.87 (d, 2H), 7.60 (d, 2H), 7.46-7.30 (m, 5H), 5.62 (s,1H), 4.88 (t, 2H), 3.96-3.85 (m, 3H), 3.65 (s, 3H), 3.28 (s, 3H),1.88-1.68 (m, 2H), 1.50-1.41 (m, 1H), 0.88 (d, 3H), 0.57 (d, 3H).

Step 2 methyl(2S)-2-{[(R)-(4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanoate

A mixture of3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridiniumbromide from example 41 step 1 (870 mg, 1.64 mmol), ethanol (50 mL),acetic acid (197 mg, 3.28 mmol) and platinum oxide (hydrated) 79-84% (63mg) was hydrogenated at 60 psi for 18 hours. The mixture was filtered,concentrated and then concentrated twice with n-heptane. The residue waschromatographed on silica gel using 10% methanol in dichloromethane toobtain the title compound as a thick oil.

MS (+APCI) 454.2 [M+1]⁺

Step 3(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide

Using the same hydrolysis and coupling procedures as described forexample 36 step 5, methyl(2S)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanoate(741 mg, 1.6 mmol) was hydrolyzed and coupled to give the title compoundas a white solid.

MS (+APCI) 478.2 [M+1]⁺

EXAMPLE 42 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)-1-oxidopiperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide

To a solution of(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-pentanamidefrom example 41 step 3 (390 mg, 0.81 mmol) in dichloromethane (12 mL) at0° C was added 77% quality 3-chloroperoxybenzoic acid (183 mg, 0.81mmol). The mixture was stirred for 5 minutes and then 5% NaHCO₃ solution(10 mL) was added with stirring. The dichloromethane layer wasseparated, dried (Na₂SO₄), filtered and concentrated. The residue waschromatographed on silica gel using 30% methanol in ethyl acetate aseluent to obtain the title compound as a foam.

MS (+APCI) 494.3 [M+1]⁺

EXAMPLE 43 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenl)methyl]oxy}pentanamideStep 1 methyl(2S)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanoate

Using the same procedure as described for example 36 step 2, methyl(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoate (2.05g, 5.25 mmol) and 3-quinolineboronic acid (1.0 g, 5.78 mmol) werecoupled to give the title compound as an oil.

MS (+APCI) 440.1 [M+1]⁺

Step 2(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methy]oxy}pentanamide

Using the same hydrolysis and coupling procedures as described for thepreparation of for example 36 step 5, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanoate(500 mg, 1.1 mmol) was hydrolyzed and coupled to give the title compoundas a white solid.

MS (+APCI) 464.1 [M+1]⁺

EXAMPLE 44 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 13-(4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylguinoliniumiodide

Using the same procedure as described for example 36 step 3, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanoate(750 mg, 1.7 mmol) was converted to the title compound as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (s, 1H), 9.59 (s, 1H), 8.53 (d, 1H),8.48 (d, 1H), 8.28 (t, 1H), 8.09 (t, 1H), 7.98 (d, 2H), 7.65 (d, 2H),7.47-7.30 (m, 5H), 5.65 (s, 1H), 4.72 (s, 2H), 3.48-3.40 (m, 1H), 3.67(s, 3H), 1.86-1.68 (m, 2H), 1.50-1.43 (m, 1H), 0.89 (d, 3H), 0.68 (d,3H).

Step 2 methyl(2S)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate

Using the same procedure as described for example 39 Step 1,3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylquinoliniumiodide (1.0 g, 1.7 mmol) was hydrogenated and purified by chromatographyon silica gel using 5% ethyl acetate in hexanes to yield the titlecompound as a foam.

MS (+APCI) 458.2 [M+1]⁺

Step 3(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide

Using the same hydrolysis and coupling procedures as described forexample 36 Step 5, methyl(2S)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate(273 mg, 0.59 mmol) was hydrolyzed and coupled to give the titlecompound as a white solid.

MS (+APCI) 482.2 [M+1]⁺

EXAMPLE 45 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidoquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 40,(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanamide(126 mg, 0.27 mmol) was oxidized to give the title compound.

MS (+APCI) 480.1 [M+1]⁺

EXAMPLE 46 Synthesis of4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoicacid

(2S)-2-[(4-bromophenyl)(phenyl)methoxyl]-N-(cyanomethyl)-4-methylpentanamidefrom example 67 step 4 (1.7 g, 4 mmol), tri-n-butylamine (2.7 g, 14.7mmol, 3.7 eq), triphenylphosphine (160 mg, 0.6 mmol, 0.15 eq) bis(triphenylphosphine)palladium (11) chloride (42.5 mg, 0.06 mmol, 0.015eq) and H₂O (800 mg, 0.8 mmol, 0.2 eq) were charged in a pressure steelbomb. The apparatus was heated at 130° C. under 300 psi of carbonmonoxide for 18 hours. Crude reaction mixture was partitioned betweenethyl acetate (50 mL) and 1N HCl (25 mL). Organic fraction was washedwith brine, dried, concentrated to give a light pink oil.Chromatographed with 30% EtOAc/hexane+1% AcOH to yield a yellow oil.

MS (−ESI) 379.2 [M−1]⁻

EXAMPLE 47 Synthesis of4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl)-3-methylbutyl)oxy](phenyl)methyl]-N-methoxy-N-methylbenzamide

To a solution of4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoicacid from example 46 (40 mg, 0.105 mmol) and N,O-dimethylhydroxylaminehydrochloride (10.3 mg, 0.105 mmol, 1 eq) in 1 mL DMF were added HATU(40 mg, 0.105 mmol, 1 eq), triethylamine (32 mg, 0.315 mmol, 3 eq). Themixture was stirred at room temperature for 18 hours, then poured into ahalf saturated solution of NaHCO3 (5 mL). It was extracted with EtOAc(2×10 mL); washed organic fraction with brine, concentrated to give theproduct.

MS (+APCI) 424.2 [M+1]⁺

EXAMPLE 48 Synthesis of4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-N,N-dimethylbenzamide

Using the same coupling procedure as described for example 47,4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoicacid (51 mg, 0.134 mmol) was reacted with dimethylamine hydrochloride(11 mg, 0.134 mmol, 1 eg) to give the title compound as an oil afterchromatography with 25% acetone/toluene.

MS (+APCI) 408.2 [M+1]⁺

EXAMPLE 49 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-[[4-(morpholin-4-ylcarbonyl)phenyl](phenyl)methoxy]pentanamide

Using the same coupling procedure as described for example 47,4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl)}-3-methylbutyl)oxy](phenyl)methyl]benzoic acid (39 mg, 0.102 mmol) was reacted with morpholine (8.9 mg,0.102 mmol) 1 eg) to give the title compound as an oil afterchromatography with 50% EtOAc/toluene+2% Et₃N.

MS (−ESI) 448.2 [M−1]⁻

EXAMPLE 50 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylthio)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamide

(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamidefrom example 68 (150 mg, 0.361 mmol), 4-(methylthio)phenyl boronic acid(67 mg, 0.398 mmol, 1.1 eg),[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II)comnplex)(7.9 mg, 0.011 mmol, 0.03 eg), potassium iodide (180 mg, 1.08 mmol, 3eg), potassium carbonate (149 mg, 1.08 mmol, 3 eg) were mixed togetherin anisole (5 mL). The reaction mixture was degased 3× with nitrogen,then heated at 90° C. under latm of CO for 18 hours. The crude reactionmixture was concentrated under high vacuum and the residue waschromatographed with 30% EtOAc/hexane to give the title compound.

MS (+ESI) 487.1 [M+1]⁺

EXAMPLE 51 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylsulfonyl)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamide

To a solution of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylthio)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamidefrom example 50, (30 mg, 0.062 mmol) in dichloromethane (5 mL) was addedm-chloroperoxybenzoic acid (29 mg, 77% purity, 0.130 mmol, 2.1 eg) andit was stirred at room temperature for 1 hour. Reaction mixture was thenwashed with 5% NaHCO3, dried, concentrated to dryness, chromatographedwith 50% EtOAc/hexane+2% dichloromethane to yield the title compound.

MS (−ESI) 517.1 [M−1]⁻

EXAMPLE 52 Synthesis of(2S)-2-{[(R)-[4-(1,1′-biphenyl-4-ylcarbonyl)phenyl](phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

Using the same procedures as described for the example 50,(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide(105 mg, 0.253 mmol) was reacted with 1,1′-biphenyl-4-ylboronic acid (50mg, 0.253 mmol, 1 eg) to give the title compound after chromatographywith 20% EtOAc/hexane.

MS (−APCI) 515.5[M−1]⁻

EXAMPLE 53 Synthesis of(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 Synthesis of (5-bromootridin-2-yl)(phenyl)methanol

2,5 dibromopyridine (15.0 g, 63.3 mmol) was added to toluene (450 ml)and it was cooled at −70° C. BuLi (1.6 M in hexanes)(41 ml, 66.5 mmol,1.05 eg) was added dropwise over 1 hour, then reaction mixture wasstirred at −70° C. for another hour. Benzaldehyde (7.4 g, 69.6 mmol, 1.1eg) dissolved in toluene (5 mL) was added slowly. The mixture wasstirred at −70° C. for 30 min., then warmed to 0° C. Quenched with SatNH4Cl (200 mL) and phases partitioned. Aqueous phase was extracted withEtOAc (100 mL) and combined organic washed with brine, dried,evaporated. Residue was chromatographed with 15% EtOAc/hexane to yieldthe title compound.

Step 2 Synthesis of (5-bromopyridin-2-yl)(phenyl)methyl 2,2,2-trichloroethanimidoate

To a solution of (5-bromopyridin-2-yl)(phenyl)methanol from example 53step 1 (2 g, 7.6 mmol) in Et2O (20 mL) was added NaH (30 mg; 60%dispersion in oil, 0.76 mmol, 0.1 eg). The resulting suspension wascooled to 0° C. and trichloroacetonitrile (1.1 g, 7.6 mmol, 1 eg) wasadded dropwise. Reaction mixture was stirred at 0° C. for 15 min., thenat room temperature for 30 min. The precipitate was filtered and washedwith Et₂O.

Step 3 Synthesis of(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanarmide

To a solution of (5-bromopyridin-2-yl)(phenyl)methyl2,2,2-trichloroethanimidoate from example 53 step 2 (2 g, 4.9 mmol) in1,2-dichloroethane (50 mL) was added(2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide (830 mg, 4.9 mmol, 1eg) and camphor sulfonic acid (114 mg, 0.49 mmol, 0.10 eg). Thesuspension was heated to reflux for 18 hours, then concentrated todryness. Residue was chromatographed with 25% EtOAc/hexane to yield thetitle compound.

MS (−ESI) 414, 416 [M−1]⁻

EXAMPLE 54 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[5-(4-piperazin-1-ylphenyl)pyridin-2-yl]methoxy}pentanamide

(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamidefrom example 53 step 3 (156 mg, 0.375 mmol), 4-piperazine-1-ylphenylboronic acid (100 mg, 0.413 mmol, 1.1 eg),[1,1′-Bis(diphenylphosphino)-ferrocene dichloropalladium II complex withCH₂Cl₂ (13.7 mg, 0.0187 mmol, 0.05 eg), sodium carbonate (2M soln, 750uL, 1.5 mmol, 4 eg) were mixed together in DMF (5 mL). The reactionmixture was degased 3× with N₂, then heated to 90° C. for 5 hours. Aftercooling, the mixture was evaporated under high vacuum and residue waschromatographed with a mixture of dichloromethane/methanol/ammoniumhydroxide (90:9:1) to give the title compound.

MS (−ESI) 496.2 [M−1]⁻

EXAMPLE 55 Synthesis of(2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamide

Using the same procedure as described for example 54,(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide(190 mg, 0.456 mmol) was reacted with 4-(methylthio)phenyl boronic acid(84 mg, 0.502 mmol, 1.1 eg) to give respectively the less polar isomerand the more polar isome after chromatography with 30% EtOAc/hexane.

MS(−ESI) 458.2 [M−1]⁻

EXAMPLE 56 Synthesis of (2S)-N-(cyanomethyl)-4-methyl-2-{[(R orS)-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide

To a solution of(2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamidefrom example 55 (112 mg, 0.244 mmol) in dichloromethane (20 mL) at 0° C.was added portionwise m-chloro-peroxybenzoic acid (109 mg, 77% purity,0.488 mmol, 2 eq). The reaction mixture was then allowed to stir at roomtemperature for 30 min. After washing the mixture with 5% NaHCO3 andevaporation, the residue was chromatographed with 60% EtOAc/hexane+1%dichloromethane to give the title compound.

MS (+ESI) 492.1 [M+1]⁺

EXAMPLE 57 Synthesis of (2S)-N-(cyanomethyl)-4-methyl-2-{[(R orS)-{5-[4-methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 56,(2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamidefrom example 55 (30 mg, 0.065 mmol) was reacted withm-chloroperoxybenzoic acid (29 mg, 77% purity, 0.13 mmol, 2 eg) to givethe title compound.

MS (+ESI) 492 [M+1]⁺

EXAMPLE 58 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-[{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2-yl}(phenyl)methoxy]pentanamide

The title compound was obtained from over oxidation of(2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamidefrom example 55 during the preparation of example 57. The title compoundwas recovered by chromatography with EtOAc.

MS (+ESI) 508 [M+1]⁺

EXAMPLE 59 Synthesis of(2S)-2-[(4-bromothien-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide Step 1 Synthesis of (4-bromothien-2-yl)(phenyl)methanol

2,4 dibromothiophene (3g, 12.4 mmol) was dissolved in Et₂O (50 mL) andcooled to −78° C. BuLi (1.6 M in hexanes)(8.1 mL, 13 mmol, 1.05 eg) wasadded dropwise over 20 min. then the yellow solution was stirred at −78°C. for 1 hour. Benzaldehyde (1.45 g, 13.64 mmol, 1.1 eg) dissolved inEt2O (15 mL) was added dropwise at a rate to maintain internaltemperature <−70° C., then reaction mixture was allowed to warm slowlyto 0° C. Quenched with Sat NH₄Cl (50 mL) and phases partitioned. Organicfraction was washed with brine, dried, concentrated. Residue waschromatographed with 10% EtOAc/hexane to yield the title compound as apale yellow solid.

Step 2 Synthesis of (4-bromothien-2-yl)(phenyl)methyl2,2,2-trichloroethanimidoate

Using the same procedure as described for example 53, Step 2(4-bromothien-2-yl)(phenyl)methanol (1 g, 3.7 mmol) provided the titlecompound as an orange oil after chromatography with 5% EtOAc/hexane.

Step 3 Synthesis of(2S)-2-[(4-bromothien-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same procedure as described for example 53, Step 3,(4-bromothien-2-yl)(phenyl)methyl 2,2,2-trichloroethanimidoate (970 mg,2.35 mmol) provided the title compound after chromatography with 25%EtOAc/hexane.

MS (−ESI) 419, 421 [M−1]⁻

EXAXPLE 60 Synthesis of(2S)-2-[(5-bromo-1-oxidopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

Using the same procedure as described for example 40,(2S)-2-[(5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide(51 mg, 0.123 mmol) was oxidized to give the title compound afterchromatography with 50% EtOAc/hexane.

MS (−ESI) 430,432 [M−1]⁻

EXAMPLE 61 Synthesis of(2S)-N-(cyanomethyl)-4methyl-2-{[(R)-[4-(1-methylpiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 1 methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanoate

Using the same procedure as described example 36 Step 2, methyl(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methyl pentanoate (2.7g, 6.8 mmol) was coupled with pyridine-4-boronic acid (920 mg, 7.5 mmol,1.1 eg) to yield the title compound after chromatography with 30%EtOAc/hexane.

Step 24-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide

Using the same procedure as described for example 36 Step 3, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanoate(757 mg, 1.95 mmol) provided the title compound.

Step 3 methyl(2S)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanoate

Using the same procedure as described example 39 Step 1,4-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide (460 mg, 0.866 mmol) gave the title compound.

Step 4(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide

Using the same procedure as described example 36 Step 5,4-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-methylpyridiniumiodide (354 mg, 0.88 mmol) gave the title compound as a light beigesolid after stirring in 20% EtOAc/hexane for 2 hours.

MS (−APCI) 432.2 [M−1]⁻

EXAMPLE 62 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamideStep 14-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridiniumbromide

Using the same procedure as described for example 41, Step 1, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanoate(580 mg, 1.5 mmol) provided the title compound.

Step 2(2S)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanoate

Using the same procedure as described for example 41, Step 2,4-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridiniumbromide (792 mg, 1.5 mmol) provided the title compound afterchromatography with 5% methanol/chloroform.

Step 3(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide

Using the same procedure as described for example 36, Step 5,(2S)-2-}[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)oxy}-4-methylpentanoate(417 mg, 0.92 mmol) was hydrolyzed and coupled to give the titlecompound after chromatography with dichloromethane/methanol/ammoniumhydroxide (90:9:1).

MS (−APCI) 476.4 [M−1]⁻

EXAMPLE 63 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methyl-1-oxidopyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 1 methyl(2S)-4-methyl-2-{[(R)-[4-(6-methylpyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate

Using the same procedure described for example 36, Step 2,methyl-(2S)-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoate(1.6 g, 4.1 mmol) was coupled with dimethyl 6-methylpyridin-3-ylboronate (1 g, 6.0 mmol, 1.5 eg) to yield the title compound as a yellowoil after chromatography with 30% EtOAc/hexane.

Step 2 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methylpyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 36, Step 5, methyl(2S)-4-methyl-2-{[(R)-[4-(6-methylpyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanoate(202 mg, 0.5 mmol) was hydrolyzed and coupled to give the title compoundas a white solid after chromatography with 50% EtOAc/hexane.

Step 3(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methyl-1-oxidopyridin-3-yl)phenyl](phenol)methyl]oxy}pentanamide

Using the same procedures as described for example 40,(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methylpyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide(100 mg, 0.23 mmol) was oxidized to give the title compound as a whitesolid.

MS (+APCI) 444.1 [M+1]⁺

EXAMPLE 64 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-4-yl)phenyl](phenyl)methyl]oxy}pentanamideStep 1(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 36 Step 5, methyl(2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl) methyl]oxy}pentanoate(525 mg, 1.35 mmol) was hydrolyzed and coupled to give the titlecompound after chromatography with 50% EtOAc/hexane.

Step 2(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-4-yl)phenyl)](phenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 40(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanamide(117 mg, 0.28 mmol) was oxidized to give the title compound as a lightyellow solid.

MS (+APCI) 430.1 [M+1]⁺

EXAMPLE 65 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1-oxidopiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide

Using the same procedure as described for example 40,(2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin)-4-yl)phenyl](phenyl)methyl]oxy}pentanamide(80 mg, 0.185 mmol) was oxidized to give the title compound as a foamysolid.

MS (+APCI) 450.2 [M+1]⁺

EXAMPLE 66 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)-1-oxidopiperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide

Using the same procedure as described for example 40,(2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide(75 mg, 0.157 mmol) was oxidized to give the title compound afterchromatography with 50% methanol/acetone.

MS (+ESI) 494.3 [M+1]⁺

EXAMPLE 67 Synthesis of(2S)-2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamideStep 1 (2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide

L-leucic acid (85 g, 0.643 mole), amino acetonitrile hydrochloride (68g, 0.734 mole, 1.14 eg), pyBOP (319 g, 0.612 mole, 0.95 eg) were mixedtogether in DMF (1 L) and cooled at 0° C. Triethylamine (149 g, 1.47mole, 2.4 eg) was added dropwise at a rate to maintain internaltemperature ≦20° C. Reaction mixture was then allowed to warm to roomtemperature and stirred for 18 hours. Reaction mixture was pouredportionwise into saturated NaHCO₃ (4 L) and extracted with EtOAc (2×1L). Half saturated NaCl solution was added to help partition. Combinedorganic fractions were washed with brine, 0.5 N HCl, brine, dried andevaporated to give a dark red oil. The latter was passed through asilica plug with 50% EtOAc/hexane to give of the title compound.

Step 2 (4-bromophenyl)(phenyl)methanol

To a solution of (4-bromophenyl)(phenyl)methanone (200 g, 0.766 mole) inTHF (600 mL) and methanol (400 mL) was added in portions pulverizedsodium borohydride (29 g, 0.766 mole) while maintaining the internaltemperature between 3° C. and 10° C. After stirring for an additional 15minutes, acetone (125 mL) was added and the mixture stirred for asubsequent 10 minutes. The solution was concentrated and the residuepartitioned between water (250 mL) and ethyl acetate (1.0 L). Theorganic layer was separated, dried (Na₂SO₄), filtered and concentrated.The residue was pumped on by high vacuum for 18 hours to give the titlecompound as an oil.

Step 3 (4-bromophenyl)(phenyl)methyl 2,2,2-trichloroethanimidoate

(4-bromophenyl)(phenyl)methanol from example 67 step 2 (175 g, 0.665mol) was dissolved in Et₂O (700 mL) and sodium hydride (2.66 g of 60%dispension in oil, 0.067 mol, 0.1 eg) was added. Reaction mixture wascooled to 0° C and trichloroacetonitrile (96 g, 0.665 mol, 1 eg) wasadded dropwise over 15 min. Reaction mixture was allowed to warm to roomtemperature and stirred for 1.5 hours. Mixture was evaporated to drynessand solid was stirred in hexane for 18 hours. The solid was filtered togive the product.

Step 4(2S)-2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide

(2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from example 67 step1 (22.5 g, 0.132 mol) and (1R)-(-1-10-camphorsulfonic acid (2.85 g,0.012 mol, 0.1 eg) were added to 1,2-dichloroethane (135 mL) and thesuspension was heated to 50° C. (4-bromophenyl)(phenyl)methyl2,2,2-trichloroethanimidoate (50 g, 0.123 mol, 0.93 eg) was addedportionwise over 15 min. then reaction mixture was stirred at 50° C. for10 min. The reaction was repeated with 2×50 g and 1×69 g of(4-bromophenyl)(phenyl)methyl 2,2,2 trichloroethanimidoate, using sameproportions of other reagents. All the batches were combined andevaporated to give a dark red oil (320 g). The latter was dissolved intoluene (600 mL); insoluble material was filtered off and the filtratewas charged on a chromatography column, eluted with 5% EtOAc/toluene togive the title compound.

MS (−ESI) 413 415 [M−1]⁻

EXAMPLE 68 Synthesis of(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide

(2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acidfrom Step 2, Example 1, (46.5 g, 123 mmol) was dissolved in DMF (200mL). To this mixture was added HATU (56.7 g, 149 mmol, 1.2 eg), Et₃N(57.7 g, 570 mmol, 4.6 eg), then added at 0° C. aminoacetonitrilehydrochloride (13.5 g, 146 mmol, 1.19 eg). The resulting reactionmixture was stirred at room temperature for 3 hours; then poured into 1L of half saturated sodium bicarbonate. The aqueous phase was extractedwith EtOAc (2×500 mL). Organic fraction was washed with brine (200 mL),INHCl (200 mL), brine (200 mL), 0.5 N NaOH (300 mL), brine (200 mL).Solvent was evaporated under reduced pressure and the resulting dark redoil which was chromatographed with 20% EAlhexane to give the titlecompound.

EXAMPLE 69 Synthesis of2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamideStep, 1 methyl 2-bromo-4-methylpentanoate

To a solution of 2-bromo-4-methylpentanoic acid (9.86 mmol, 1.31 g) inCH₂Cl₂ (100 mL), was added slowly a solution of diazomethane until nobubbles appears. The mixture was stirred at r.t. for 0.25 h. Thevolatiles were removed under reduced pressure to leave a yellow liquid.The crude methyl ester was used without further purification.

Step 2 1-(4-bromophenyl)-2,2,2-trifluoroethanol

To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (37.7 mmol,8.86 g) in methanol (89 mL) at 0° C., was added sodium borohydride(39.6, 1.50 g). The mixture was stirred for 1 h. HCl 10% (100 mL) wasadded and the mixture was stirred for 0.25 h. The mixture was extractedwith CH₂Cl₂. The combined extracts were dried over anhydrous MgSO₄ andconcentrated under reduced pressure. The crude alcohol was used withoutfurther purification.

Step 3 methyl2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-4-methylpentanoate

Sodium hydride (60% W, 2.16 mmol, 87 mg) was suspended in dry THF andcooled to 0° C. A solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanolfrom example 69 step 2 was added slowly and stirred at 0° C. over 0.75h. A solution of methyl 2-bromo-4-methylpentanoate from example 69 step1 was added and the mixture was allowed to warmed to r.t. and stirredovernight. The reaction was treated with 0.1 N aqueous hydrochloricacid, diluted with diethyl ether and ethyl acetate. The phases areseparated and the organic layer was washed with 0.1N aqueoushydrochloric acid then brine and dried over magnesium sulfate. Thevolatiles were removed unde reduced pressure to yield methyl4-methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoate that was usedwithout further purification.

Step 4 4-methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoic acid

To a suspension of methyl4methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoate from example 69step 3 (0.63 mmol, 241 mg) in pyridine (7 mL), lithium iodide (1.26mmol, 168 mg) was added and the mixture was heated at 140° C. for 24 h.The mixture was cooled to r.t. HCl 10% (20 mL) was added and HCl 12 Nwas added until pH 1. The mixture was extracted with ethyl acetate (50mL) 3×. The combined extracts were dried over anhydrous MgSO₄ andconcentrated. The crude title acid was used without furtherpurification.

Step 52-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide

To a solution of the4-methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoic acid from example69 step 4 (0.18 mmol, 68 mg) in DMF (2.5 mL) was added aminoacetonitrilehydrochloride (0.28 mmol, 26 mg) and HATU (0.21 mmol, 81 mg).Triethylamine (0.61 mmol, 85 μL) was added last. The mixture was stirredat r.t. overnight. Et₂O (20 mL) was added, followed by HCl 1N (10 mL).The mixture was separated. The organic exract was washed with HCl 0.1N(10 mL), water and brine. The combined extracts were dried overanhydrous MgSO₄ and concentrated. Purification: 30:70 (AcOEt:Hex.) gave2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide.

EXAMPLE 70 Synthesis of(2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamide

To a solution of2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamidefrom example 69 step 5 (4.06 mmol, 2.0 g) in Et₃N (12 mL), was addedtrimethylsilane acetylene (6.09 mmol, 861 μL) followed by palladiumtetrakis triphenylphosphine (0.08 mmol, 92 mg) and cupper iodide (0.12mmol, 23 mg). The reaction was heated at 75° C. over night. The mixturewas cooled to r.t. and extracted with Et₂O (20 mL). The phases wereseparated. The organic extract was washed with saturated aqueousammonium chloride (20 mL). The organic extracts were dried overanhydrous MgSO₄ and concentrated under reduced pressure. Purificationwith 30:70 AcOEt:Hexanes gave the title amide.

MS (−APCI) 431.2 [M−1]⁻

EXAMPLE 71 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-(4-ethynylphenyl)(phenyl)methyl]oxy}-4-methylpentanamide

To a solution of(2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamidefrom example 70 (0.12 mmol, 50 mg) in ThF:MeOH (1.3 mL: 50 uL) at 0° C.,AcOH (3 drops) was added followed by tetrabutylammoniumtriphenyldifluorosilicate (0.01 mmol, 7 mg). The mixture was stirred 20minutes at 0° C. The mixture was diluted with 1% sodium hydroxyde (3 mL)and diethlyl ether (5 mL). The phases were separated. The organic layerwas dried over anhydrous MgSO₄ and concentrated under reduced pressure.Purification: 30:70 (AcOEt:Hex.) gave the title amide.

MS (−APCI) 459.1 [M−1]⁻

EXAMPLE 72 Synthesis of(2S)-N-(cyanomethyl)-2-{[(R)-(4-cyanophenyl)(phenyl)methyl]oxy}-4-methylpentanamide

To a solution of2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamidefrom example 69 step 5 (2.03 mmol, 1.0 g) in DMF (2.5 mL), was addedzinc cyanide (1.22 mmol, 144 mg) followed by palladiumtetrakistriphenylphosphine (0.08 mmol, 92 mg). The mixture was degassedthree times via the freeze-thaw method. The mixture was heated at 80° C.over night. The next day, more zinc cyanide (0.61 mmol, 72 mg) andtetrakistriphenylphosphine (0.04 mmol, 46 mg) were added The mixture washeated at 80° C. overnight. The mixture was cooled to r.t. and dilutedwith AcOEt (20 mL). The phases were separated and the organic extractwas washed with ammonium chloride, brine. The organic layer was driedover anhydrous MgSO₄ and concentrated under reduced pressure.Purification: 50:50 (AcOEt:Hex.) gave the title amide.

MS (−APCI) 360.1 [M−1]⁻

EXAMPLE 73 Synthesis of2-{[(4-bromophenyl)(phenyl)methyl]thio}-N-(cyanomethyl)-4-methylpentanamideStep 1 methyl 2-}[(4-bromophenyl)(phenyl)methyl]thio}-4-methylpentanoate

To a solution of triisopropylsilanethiol (1.75 mL, 8.05 mmoles) and(4-bromophenyl)(phenyl)methanol from example 67 step 2 (3.5, 8.05mmoles) in 16 mL of DMF was added sodium hydride as a 60% emulsion inoil (386 mg, 9.66 mmoles). After the exotherm has passed, 1.65 mL (10mmole) of methyl 2-bromo-4-methylpentanoate was added followed by 12 mLof a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran.After stirring overnight, the reaction was diluted with diethyl ether(200 mL) and washed twice with 0.1 N HCl, twice with water and once withbrine. The organic phase was dried over magnesium sulfate andconcentrated under reduced pressure. The oil as purified by flashchromatography (9:1 hexanes to ethyl acetate) to give the title ester.

Step 2 2-}[(4-bromophenyl)(phenyl)methyl]thio}-4-methylpentanoic acid

To a solution of 1 g (2.4 mmoles) of methyl2-{[(4-bromophenyl)(phenyl)methyl]thio}-4-methylpentanoate from example73 step 2 in a ternary mixture of tetrahydrofuran, methanol and waterwas added solid lithium hydroxyde monohydrate (151 mg, 3.6 mmoles). Thereaction was stirred until disappearance of the starting material bythin layer chromatography and diluted with 1N hydrochloric acid anddichloromethane. The phases were separated and the aqueous phase waswashed twice with dichloromethane. The combined organic layers weredried over magnesium sulfate and concentrated under reduced pressure.The title acid was used without further purification.

Step 32-{[(4-bromophenyl)(phenyl)methyl]thio}-N-(cyanomethyl)-4-methylpentanamide

The procedure from step 3 example 1 was used except that2-{[(4-bromophenyl)(phenyl)methyl]thio}-4-methylpentanoic acid was usedas the carboxylic acid component to give the title compound.

MS (−ESI) 431.0 [M−1]⁻

EXAMPLE 74 Synthesis of2-{[(4-bromophenyl)(phenyl)methyl]sulfonyl}-N-(cyanomethyl)-4-methylpentanamide

To a solution of2-{[(4-bromophenyl)(phenyl)methyl]thio}-N-(cyanomethyl)-4-methylpentanamidefrom example 73 step 3 (111 mg, 0.26 mmoles) in a 1:1 mixture ofdichloromethane and methanol at 0° C. is added 318 mg (0.64 mmoles)MMPP. After stirring for 30 minutes, the reaction is partitioned betweenethyl acetate and saturated aqueous bicarbonate. The phases aeseparated, the organic layer was washed with saturated aqueousbicarbonate, water and brine successively. The organic portion is driedover magnesium sulfate and concentrated under reduced pressure. The oilwas purified via flash chromatography on silica gel to afford the titlecompound.

MS (

ESI) 463.1 [M−1]⁻

1. A compound of the formula:

wherein R¹ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and alkenyl groups are optionally substituted with halo; R² is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and alkenyl groups are optionally substituted with halo; or R¹ and R² can be taken together with the carbon atom to which they are attached to form a C₃₋₈ cycloalkyl ring wherein said ring system is optionally substituted with C₁₋₆ alkyl, hydroxyalkyl or halo; R³ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or halo; R⁴ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkenyl wherein said alkyl and alkenyl groups are optionally substituted with C₃₋₆ cycloalkyl or halo; or R³ and R⁴ can be taken together with the carbon atom to which they are attached to form a C₃₋₈ cycloalkyl ring, C₅₋₈ cycloalkenyl ring, or five to seven membered heterocycloalkyl wherein said cycloalkyl, cycloalkenyl and heterocycloalkyl groups are optionally substituted with C₁₋₆ alkyl, halo, hydroxyalkyl, hydroxy, alkoxy or keto; X is selected from the group consisting of —O—, —S—, SO₂, and —C(R⁵)(R⁶)—; R⁵ is hydrogen or C₁₋₆ alkyl; R⁶ is hydrogen or C₁₋₆ alkyl; or R⁵ and R⁶ can be taken together with any of the atoms to which they may be attached or are between them to form a 3-8 membered cycloalkyl ring system wherein said ring system is optionally substituted with C₁₋₆ alkyl or halo; R⁷ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkyloxy, nitro, cyano, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, —C(O)OR¹⁰, —C(O)R¹⁰, —C(O)OSi[CH(CH₃)₂]₃, —R¹⁰C(O)R¹³, —C(O)R¹³, —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³), —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R¹³ or C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C₁₋₆ alkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂, —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², —SO(R¹²), —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹)(R¹³), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃, heterocycloalkyl, aryl or heteroaryl; R⁸ is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkyloxy, nitro, cyano, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, —C(O)OR¹⁰, —C(O)R¹⁰, C(O)OSi[CH(CH₃)₂]₃, —R¹⁰C(O)R¹³, —C(O)R¹³, —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂, —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³), —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))(R¹³), —C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R¹³ or C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C₁₋₆ alkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR⁹, —O(aryl), —NO₂, —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², SO(R¹²), —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹)(R¹³), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃, heterocycloalkyl, aryl or heteroaryl; D is aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, C₁₋₃ alkyl or C₁₋₃ alkenyl wherein said aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups, which may be monocyclic or bicyclic, are optionally substituted on either the carbon or the heteroatom with one to three substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkyloxy, halo, keto, nitro, cyano, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl, —C(O)OR¹⁰, —C(O)OSi[CH(CH₃)₂]₃, —OR¹⁰, —C(O)R¹⁰, —R¹⁰C(O)R¹³, —C(O)R¹³, —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —SR¹², —SR¹³, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂, —SO₂R¹², —SO(R¹²), —SO₂R¹³, —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹), —SO₂N(R¹⁰)C(O)(R¹²), —SO₂(R¹⁰)C(O)N(R¹²)₂, —OSO₂R¹⁰, —N(R¹⁰)(R¹¹), —N(R¹⁰)C(O)NR¹⁰R¹³, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂R¹⁰, —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)(R¹³), R¹⁰S—, —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b))(R¹³), —C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R¹³ or —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)); wherein said alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR¹³, —NO₂, —NH₂, —NHS(O)₂R¹⁰, —R¹³SO₂R¹², —SO₂R¹², —SO(R¹²), —SO₂N(R^(c))(R^(d)), —SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, —Si(CH₃)₃, heterocycloalkyl, aryl or heteroaryl; R⁹ is hydrogen, hydroxy, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkyloxy, halo, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, —C(O)OR¹⁰, —OR¹⁰, —C(O)R¹⁰, —C(O)R¹³, —C(O)N(R¹²)(R¹²), —C(R¹⁰)(R¹¹)OH, —R¹⁰SR¹³, —R¹³, —C(R¹³)₃, —C(R¹⁰)(R¹¹)N(R¹³)₂, SR¹⁰, —SO₂R¹², —SO(R¹²), —SO₂R¹³, —SO₂N(R^(c))(R^(d)), —SO₂CH(R¹⁰)(R¹¹), —N(R¹⁰)(R¹¹), —N(R¹⁰)C(O)NR¹⁰R¹³, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)SO₂R¹⁰, —C(R¹⁰)(R¹¹)NR¹⁰C(R¹⁰)(R¹¹)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)R¹³, —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)SC(R¹⁰)(R¹¹)—, R¹⁰S—, —C(R^(a))(R^(b))NR^(a)C(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(O)C(R^(a))(R^(b))N(R^(a))(R^(b)), —C(R^(a))(R^(b))N(R^(a))C(O)R¹³; wherein said alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, —OR¹³, —NO₂, —NH₂, —NHS(O)₂R⁸, —R¹³SO₂R¹², SO₂R¹², SO(R¹²), SO₂N(R^(c))(R^(d)), SO₂N(R¹⁰)C(O)(R¹²), —C(R¹⁰)(R¹¹)N(R¹⁰)(R¹¹), —C(R¹⁰)(R¹¹)OH, —COOH, —C(R^(a))(R^(b))C(O)N(R^(a))(R^(b)), —N(R¹⁰)C(R¹⁰)(R¹¹), —NH(CH₂)₂OH, —NHC(O)OR¹⁰, Si(CH₃)₃, heterocycloalkyl, aryl or heteroaryl; R¹⁰ is hydrogen or C₁₋₆ alkyl; R¹¹ is hydrogen or C₁₋₆ alkyl; R¹² is hydrogen or C₁₋₆ alkyl which is optionally substituted with halo, alkoxy, cyano, —NR¹⁰ or —SR¹⁰; R¹³ is selected from the group consisting of hydrogen, aryl, aryl(C₁₋₄) alkyl, heteroaryl, heteroaryl(C₁₋₄)alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl(C₁₋₄)alkyl, and heterocycloalkyl(C₁₋₄)alkyl wherein said groups can be optionally substituted with halo or alkoxy; Ra is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆ alkyl)hydroxyl, —O(C₁₋₆ alkyl), hydroxyl, halo, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloalkyl, wherein said alkyl, aryl, heteroaryl, C₃₋₈ cycloalkyl and heterocycloalkyl can be optionally substituted on either the carbon or the heteroatom with C₁₋₆ alkyl or halo; Rb is hydrogen, C₁₋₆ alkyl, (C₁₋₆ alkyl)aryl, (C₁₋₆ alkyl)hydroxyl, alkoxyl, hydroxyl, halo, aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocycloaLkyl, wherein said alkyl, aryl, heteroaryl, C₃₋₈ cycloalkyl and heterocycloalkyl can be optionally substituted on either the carbon or the heteroatom with C₁₋₆ alkyl or halo; or R^(a) and R^(b) can be taken together with the carbon atom to which they are attached or are between them to form a C₃₋₈ cycloalkyl ring or C₃₋₈ heterocycloalkyl ring wherein said 3-8 membered ring system may be optionally substituted with C₁₋₆ alkyl and halo; R^(c)is hydrogen or C₁₋₆ alkyl which is optionally substituted with halo or OR¹³; R^(d)is hydrogen or C₁₋₆ alkyl which is optionally substituted with halo or OR¹³; or R^(c) and R^(d) can be taken together with the nitrogen atom to which they are attached or are between them to form a C₃₋₈ heterocycloalkyl ring which is optionally substituted with C₁₋₆ alkyl, halo hydroxyalkyl, hydroxy, alkoxy or keto; n is zero, one, two or three; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 2. The compound of claim 1 wherein R³ is H and R⁴ is C₁₋₆ alkyl which is optionally substituted with C₃₋₆ cycloalkyl or halo; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 3. The compound of claim 2 wherein R³ is H and R⁴ is isobutyl; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 4. The compound of claim 1 wherein R¹ and R² are each H; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 5. The compound of claim 1 wherein R¹ and R² can be taken together with the carbon atom to which they are attached to form a C₃₋₈ cycloalkyl ring wherein said ring system is optionally substituted with C₁₋₆ alkyl, hydroxyalkyl or halo; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 6. The compound of claim 5 wherein R¹ and R² can be taken together with the carbon atom to which they are attached to form a cyclopropyl ring wherein said ring system is optionally substituted with C₁₋₆ alkyl or halo; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 7. The compound of claim 1 wherein X is O; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 8. The compound of claim 7 wherein R⁷ is aryl, heteroaryl or C₁₋₆ haloalkyl and R⁸ is hydrogen; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 9. The compound of claim 1 wherein D is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 10. The compound of claim 9 wherein D is phenyl or pyridyl; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 11. The compound of claim 1 wherein R⁹ is aryl, heteroaryl or heterocycloalkyl, wherein wherein said groups are optionally substituted on either the carbon or the heteroatom with one to five substituents independently selected from C₁₋₆ alkyl, halo, —SO₂R¹², —SO(R¹²) or aryl; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 12. The compound of claim 1 selected from: (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4′-pyridin-4-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide; (2S)-2-({(R)-(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}oxy)-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-[4-(methylsulfonyl)phenyl](4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-[4′-(1H-imidazol-1-yl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}-4-methylpentanamide; (2S)-2-{[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[(S)-(4-bromophenyl)(mesityl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-(benzhydryloxy)-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[(S)-(4-chlorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-2-{[(S)-mesityl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}-4-methylpentanamide; 1-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)cyclohexanecarboxamide; (2S)-2-{[(1R)-1-(4-bromophenyl)-2-(4-chlorophenyl)ethyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[(R)-(4-bromophenyl)(cyclopropyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[(R)-(3-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(1-methyl-1H-pyrazol-5-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[[4-(3-chloropyrazin-2-yl)phenyl](phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[4-(1,3-thiazol-2-yl)phenyl]methoxy}pentanamide; (2S)-2-[[4′-(aminosulfonyl)-1,1′-biphenyl-4-yl](phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl](phenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-quinolin-3-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrimidin-5-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-quinolin-8-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-2-[{4-[6-(hydroxymethyl)-1-oxidopyridin-3-yl]phenyl}(phenyl)methoxy]-4-methylpentanamaide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-4-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-2-[[4-(1H-indol-4-yl)phenyl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-2-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrazin-2-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyridin-3-ylphenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-(phenyl{4-[5-(2H-tetraazol-5-yl)pyridin-3-yl]phenyl}methoxy)pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[[4-(3-methylpyridin-2-yl)phenyl](phenyl)methoxy]pentanamide; 2-{4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]phenyl}isonicotinic acid; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4-pyrimidin-2-ylphenyl)methoxy]pentanamide; ethyl 4′-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-carboxylate; 4′-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-carboxaamide; N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide; N-(cyanomethyl)-2-[(4-{[4-(2-fluoroethyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-[(4-{[4-(methylsulfonyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]pentanamide; (2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(thien-2-yl)methyl]oxy}pentanamide; (2S)-2-[(4-bromophenyl)(thien-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(pyridin-2-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxyl-N-(cyanomethyl)-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(pyridin-2-yl)methoxy]pentanamide; N-(cyanomethyl)-4-methyl-2-[(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)(1,3-thiazol-2-yl)methoxy]pentanamide; 2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-N-(cyanomethyl)-4-methylpentananide; 2-[(4-bromophenyl)(pyridin-4-yl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[1-(4-bromophenyl)ethoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[1-(4-bromophenyl)propoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[1-(4-bromophenyl)ethoxy]-N-(cyanomethyl)-4-methylpentanamide; N-(cyanomethyl)-2-[(4-fluorophenyl)(4-pyridin-4-ylphenyl)methoxy]-4-methylpentanamide; 2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide; N-(cyanomethyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpentanamide; 2-[1-(4-bromophenyl)propoxy]-N-(cyanomethyl)-4-methylpentanamide; N-(1-cyanocyclopropyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide; (2S)-N-(cyanomethyl)-2-[(4-fluorophenyl)(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide; (2S)-2-[(4-bromophenyl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(S)-phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methyl]oxy}pentanamide; N-(cyanomethyl)-4-methyl-2-[1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide; N-(cyanomethyl)-4-methyl-2-[1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide; (2S)-2-[(4-bromophenyl)(4-fluorophenyl)methoxyl-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylthio)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide; (2S)-N-(Cyanomethyl)-4-methyl-2-{[(R)-(4′-morpholin-4-yl-1,1′-biphenyl-4-yl)(phenyl)methyl]oxy}pentanamide; (2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[(4-bromophenyl)(cyclohexyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-{[1-(4-bromophenyl)-2-methylprop-2-enyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[1-(4-bromophenyl)-2-methylpropoxy]-N-(cyanomethyl)-4-methylpentanamide; 2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-(4-cyanophenyl)(phenyl)methyl]oxyl}-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-[((R)-phenyl{4-[(trimethylsilyl)ethynyl]phenyl}methyl)oxy]pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-(4-ethynylphenyl)(phenyl)methyl]oxy}-4-methylpentanamide; 2-[1-(4-bromophenyl)-2,2,2-trifluoroethdxy]-N-(cyanomethyl)-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-[2,2,2-trifluoro-1-(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)ethoxy]pentanamide; 2-{[(S)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; 2-[(4-bromophenyl)(phenyl)methoxyl-N-(cyanomethyl)-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-[phenyl(4-pynidin-4-ylphenyl)methoxy]pentanamide; N-(cyanomethyl)-4-methyl-2-[phenyl(4′-piperazin-1-yl-1,1′-biphenyl-4-yl)methoxy]pentanamide; (2R)-2-[(4-bromophenyl)(4-fluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4′-[4-(methylsulfonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}(phenyl)methyl]oxy}pentanamide; 2-{[(4-bromophenyl)(phenyl)methyl]thio}-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4′-(4-methylpiperazin-1-yl)-1,1′-biphenyl-4-yl](phenyl)methyl]oxy}pentanamide; N-(cyanomethyl)-4-methyl-2-(2,2,2-trifluoro-1-{4′-[4-(methylsulfonyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}ethoxy)pentanamide; 2-[(4-bromophenyl)(2,4,6-trifluorophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[bis(4-bromophenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-4-ylphenyl)methyl]oxy}pentanamide; 4-{4′-[(R)-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-1,1′-biphenyl-4-yl}-1,1-dimethylpiperazin-1-ium iodide; (2S)-N-(cyanomethyl)-2-{[(R)-{4′-[4-(2-hydroxyethyl)piperazin-1-yl]-1,1′-biphenyl-4-yl}(phenyl)methyl]oxy}-4-methylpentanamide; 2-{[(4-bromophenyl)(phenyl)methyl]sulfonyl}-N-(cyanomethyl)-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-{2,2,2-trifluoro-1-[4′-(methylthio)-1,1′-biphenyl-4-yl]ethoxy}pentanamide; 2-[1-(4-bromophenyl)-2,2,2-trifluoroethoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide; N-(cyanomethyl)-4-methyl-2-{2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethoxy}pentanamide; 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy(phenyl)methyl]-N-methoxy-N-methylbenzamide; 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]-N,N-dimethylbenzamide; (2S)-N-(cyanomethyl)-4-methyl-2-[[4-(morpholin-4-ylcarbonyl)phenyl](phenyl)methoxy]pentanamide; 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoic acid; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylthio)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-{4-[4-(methylsulfonyl)benzoyl]phenyl}(phenyl)methyl]oxy}pentanamide; (2S)-2-{[(R)-[4-(1,1′-biphenyl-4-ylcarbonyl)phenyl](phenyl) methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide; (2S)-2-[{5-bromopyridin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{phenyl[5-(4-piperazin-1-ylphenyl)pyridin-2-yl]methoxy}pentanamide; (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylthio)phenyl]pyridin-2-yl}(phenyl)methoxy]pentanamide; (2S)-N-(cyanomethyl-4-methyl-2-{[R or S)-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl-4-methyl-2-{[(R or S)-{5-[4-methylsulfonyl)phenyl]pyridin-2-yl}(phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl-4-methyl-2-[{5-[4-(methylsulfonyl)phenyl]-1-oxidopyridin-2-yl}(phenyl)methoxy]pentanamide; (2S)-2-[(4-bromothien-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methyl pentanamide; (2S)-2-[(5-bromo-1-oxidopyrdin-2-yl)(phenyl)methoxy]-N-(cyanomethyl)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methylpiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl}(phenyl)methyl]oxy)-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(6-methyl-1-oxidopyridin-3-yl)phenyl](phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-4-yl)henyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1-oxidopiperidin-4-yl)phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)-1-oxidopiperidin-4-yl]phenyl}(phenyl)(phenyl)methyl]oxy-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(5-methylcyclohex-1-en-1-yl)phenyl(phenyl)methyl]oxy}pentanamide; 3-{4-[(R)-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]phenyl}-1-methylpyridinium iodide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-(4-(1-methylpiperidin-3-yl)phenyl](phenyl)methyl]oxy)pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidopyridin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-quinolin-3-ylphenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-[4-(1-oxidoquinolin-3-yl)phenyl](phenyl)methyl]oxy}pentanamide; (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)-1-oxidopiperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(1-hydroxycyclopropyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-4-methyl-2-{(R)-phenyl[4′-(2,2,2-trifluoro-1-hydroxyethyl)biphenyl-4-yl]methoxy}pentanamide; (2S)-2-[(R)-[4′-(1-amino-2,2,2-trifluoroethyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide; 1-{4′-[(R)-[((1S)-1-{[(1-cyanocyclopropyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]biphenyl-4-yl}cyclopropanecarboxylic acid; 2-{4′-[(R)-[((1S)-1-{[(1-cyanocyclopropyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]biphenyl-4-yl}-2-hydroxypropanoic acid; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(2-hydroxyethyl)biphenylyl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-{4′-[cyclopropyl(hydroxy)methyl]biphenyl-4-yl}(phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1-hydroxyethyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1-hydroxy-1-methylethyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[3′-(1cyanocyclopropyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide; (2S)-N-(1-cyanocyclopropyl)-2-[(R)-[4′-(1cyanocyclopropyl)biphenyl-4-yl](phenyl)methoxy]-4-methylpentanamide; (2S)-2-[(R)-[3′,4′-bis(1-hydroxy-1-methylethyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide; (2S)-2-[(R)-[3′,4′-bis(1-hydroxycyclopropyl)biphenyl-4-yl](phenyl)methoxy]-N-(1-cyanocyclopropyl)-4-methylpentanamide; and the pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof.
 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, and a pharmaceutically acceptable carrier.
 14. A pharmaceutical composition made by combining a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, and a pharmaceutically acceptable carrier.
 15. A process for making a pharmaceutical composition comprising combining a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, and a pharmaceutically acceptable carrier.
 16. A method of inhibiting cathepsin activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to claim
 1. 17. The method according to claim 16 wherein the cathepsin activity is Cathepsin K activity.
 18. A method of treating of preventing a disease selected from: osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy or multiple myeloma in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim
 1. 19. The method of treating or preventing bone loss in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim
 1. 20. A method of treating or preventing osteoporosis in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim
 1. 21. A method of treating cathepsin dependent conditions in a mammal in need thereof by administering to the mammal a therapeutically effective amount of a compound according to claim
 1. 22. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.
 23. A method of treating osteoporosis comprising a compound of claim 1 and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.
 24. A method of treating bone loss comprising a compound of claim 1 and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.
 25. A pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, and another agent selected from: an organic bisphosphonate, an estrogen receptor modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, and the pharmaceutically acceptable salts and mixtures thereof.
 26. A compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, for use in inhibiting cathepsin activity.
 27. A compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, for use in treating or preventing osteoporosis.
 28. Use of a compound any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, in the manufacture of a medicament for inhibiting cathepsin activity.
 29. Use of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof, in the manufacture of a medicament for treating or preventing osteoporosis. 